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From Embryonic Stem Cells to Human Cloning: How has Assisted Reproductive Medicine Changed Regenerative Medicine?

In the previous message, I talked about the negative and positive aspects of assisted reproductive medicine today. In this message, I would like to discuss the wide-ranging impact that in vitro fertilization, the main method of assisted reproductive medicine, is having on regenerative medicine.

Regenerative medicine generally refers to using cells and genes to artificially create tissues and organs and then transplanting them to regenerate physiological functions in patients.

Many people suffer from the loss or failure of tissues or organs as a result of a congenital disorder, illness or accident. While treatment also aims to enhance the innate self-organizing ability of the body to repair systems and organs to normal structure and function, in most cases, it must rely on transplants from donors. With transplants from donors, however, there is the problem of rejection and also a limit to the number of available organs and tissues. Regenerative medicine is one answer to this problem.

Specifically, this refers to efforts to culture, for example, skin for the treatment of burns, cornea for cataracts, myocardial cells for myocardial disorders, bone and cartilage for motor disorders, neurocytes for neurological disorders, insulin-secreting cells for diabetes, among others. Some of these efforts have already been put to practice use.

What role does in vitro fertilization play in regenerative medicine? First, let's look at the process of in vitro fertilization. The ovum is surgically extracted and transferred to a Petri dish, to which sperm is added, thereby resulting in a fertilized egg. This is then inserted into the mother's uterus, according to a method of artificial insemination, which leads to pregnancy and birth.

In other words, in in vitro fertilization, the process that takes place naturally in the woman's body, from fertilization up to just before implantation of the fertilized egg in the endometrium, is achieved externally. The success rate, however, is only about 20%, but this is not so surprising, given how little we still know about how life begins and develops in the woman's body.

Even in the Petri dish, the fertilized egg created through in vitro fertilization continues to divide, with the number of cells doubling quickly. As the cells multiply, this cell mass becomes an embryo and eventually a fetus. The cells in the outer cell mass become the placenta while the cells in the inner cell mass are pluripotent, meaning that they have the latent ability to differentiate and develop into all the different organs and tissues of the embryo's body. These are called embryonic stem cells, or ES cells.

At this stage of development, this cell mass is called an embryo, which is the product of the fertilized egg undergoing cell division and propagation prior to becoming a fetus. By culturing ES cells and manipulating the genes in their nuclei, it is possible to develop them into the necessary tissues or organs.

In the 1920s, it was found that in the early phase of the development of the embryo, an area called the dorsal lip, which determines the direction of cell differentiation, begins to form. At present, experiments have succeeded in generating different tissues and organs by exposing ES cells to activin, a particular protein molecule that is secreted from this area. Wondrously, through varying concentrations of activin or combination with an organic acid, for example, cells are differentiated into various tissue or organs, such as kidneys, the pancreas, muscles, and blood corpuscles, etc.

Moreover, ES cells in the early stages can also develop into complete organisms. This is also indicated by the high incidence of identical twins and triplets or multiple embryos that occurs in in vitro fertilization. This is because these ES cells are capable of developing into an infant in the body. Considering also the fact that the frequency of identical twins is no more than 0.5% of natural pregnancies, there are still a number of issues that we must consider in this kind of artificial intervention.

From the above, it is clear that in order to make tissues and organs for regenerative therapy from human ES cells, we need to establish a method of selecting and inducing genetic material in the cell nucleus. Researchers all over the world are now competing to resolve this issue.

In the past, it was thought that pluripotent cells like ES cells only existed in the fetus or neonate, not in adults, but research over the past decade has found them in our tissues and organs as well. These are called somatic stem cells. Our bodies seem to be equipped with the ability to repair and regenerate malfunctioning parts, whenever and wherever necessary, in the event of an emergency.

Bone marrow cells are among the most typical somatic stem cells--they are comparatively plentiful and often used in bone marrow transplants to treat leukemia, etc. The culturing of the skin, muscles, blood vessels, etc., has shown that somatic stem cells are found in these tissues as well. Compared with ES cells, however, somatic stem cells create cells that are more differentiated and less pluripotent, which poses limitations on their use in yielding tissues and organs.

Using human ES cells to create tissues and organs is extremely important in transplants, the main technique involved in regenerative medicine. This is because using the patient's ES cells prevents transplant rejection. In reality, a number of problems remain and regenerative medicine still has a long way to go.

For example, even if the surplus fertilized eggs left over from in vitro fertilization are used, we cannot avoid bioethical questions regarding "the beginning of human life" insofar as they are fertilized eggs. The challenge was then to make human ES cells without using fertilized eggs, and this resulted in a stem cell called the induced pluripotent cell or iPS cell. It was discovered that by introducing four genes into the nucleus and inducing over-expression, human somatic cells would revert to an undifferentiated state, becoming stem cells that are pluripotent. In terms of bioethical issues, this method is far less controversial than using surplus fertilized eggs. Being able to derive iPS cells from one's own skin cells has opened up promising possibilities in regenerative medicine.

Moreover, when taken to the extreme, regenerative medicine could lead to human cloning. We can imagine cases in which human clones could be created to increase strong soldiers or superior astronauts or out of a wish by terminally ill patients to prolong what little life they have left. Of course, such attempts would be taboo.

Cloning technology began with Dolly, the sheep that was the world's first animal to be cloned from an adult somatic cell, as reported in the periodical Nature 1997. In the case of Dolly, the nucleus was removed from a sheep cell, inserted in another sheep's egg to replace its removed nucleus and then cultured. After it was implanted into a surrogate mother's uterus, the egg began to divide and grow into a fetus, and was eventually born as a clone. The primary material in egg was activated by genes in the nucleus of the adult sheep, which then developed into an embryo and the world's first cloned sheep.

In this way, assisted reproductive medicine, which manipulates the birth of human life, has worked to advance regenerative medicine. As it continues to do so, we can expect it to pose large questions that will change our notion of what human life should be.

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