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1. Cloning research:

   Advanced Cell Technology has initiated dozens of clone pregnancies in cows and some in pigs. The company says it anticipates the first births in the near future. For these clones, the donor cells were fibroblasts taken from fetuses. The genomes of these cells can be relatively easily and precisely manipulated through a technique known as targeted gene replacement. The company claims to have developed the ability to produce transgenic animals using fetal fibroblast nuclear transfer.

2. More cloning research:

   Roslin is attempting to compare the level and timing of gene expression in cloned embryos to develop alternative ways of measuring the efficiency of reprogramming and provide an easier means of distinguishing between normal and abnormal embryos. Many of the abnormalities in cloned embryos and foetuses also occur after embryo culture in ruminants. The expression of most genes reflects contributions from both copies of the gene, but over fifty genes have been identified in which only the gene on the maternally or paternally derived chromosome is active. Such 'imprinting' is determined during gametogenesis often by changes in the methylation state of the gene. Recent observations at Roslin have shown that sheep fetuses developing after embryo culture have abnormally low levels of expression of the imprinted gene coding for IgF2 receptor and that this is associated with a decrease in methylation of the gene. A recent study by Korean researchers (Kang et al., 2001) showed aberrant methylation patterns in various regions of the genome in cloned bovine embryos, indicating widespread impairment of epigentic reprogramming. This observation suggests that other imprinted genes might contribute to abnormal development of cloned embryos. Methylation is thought to be critically important in the regulation of early development, and the mechanisms that regulate DNA methylation are being studied further in clones and during normal development.

3. Stem cells and degenerative diseases:

   Many degenerative human diseases cause damage to cells that are not normally repaired or replaced, including liver damage (as a result of hepatitis or substance abuse), heart attack, Parkinson's disease, leukemia and diabetes. There is no fully effective treatment for any of these diseases, but experimental studies in animals and humans have suggested that these diseases might be treatable by transplantation of healthy cells. The challenge for biologists is to provide sufficient cells of the required type to make such treatments practical. The cells should be immunologically matched to the patient, have a normal life span, and be able to replace the lost function after introduction into one or a small number of sites in the body. In principle, embryo stem cells could provide a source for all of the different cell types and tissues needed. Cell lines might be obtained from surplus embryos donated after successful IVF treatment, but they would be immunologically different from most patients. The impact of this difference might vary with different conditions. In the brain, where immune rejection is less effective, it might be that no immunosuppressive drugs would be required, or perhaps only a low dose. When cells are transplanted to other sites, the patient would have to choose between the disadvantages of the initial condition and a lifetime of taking immunosuppressive drugs (and the resulting greater vulnerability to infections and cancer). Completely histocompatible cells could be obtained if stem cells were derived from embryos produced by nuclear transfer from one of the patient's own cells. Such "therapeutic cloning" would require large numbers of oocytes for use as recipients. Oocytes might be obtained (with permission) during surgery carried out for other reasons or obtained from ovarian tissue matured in culture. There are, however, immense practical limitations to these approaches, particularly if large numbers of patients are to be treated.

4. Introduction to stem cells:

   What is a stem cell? Stem cells have the ability to divide for indefinite periods in culture and to give rise to specialized cells. Human development begins when a sperm fertilizes an egg and creates a single cell that has the potential to form an entire organism. This fertilized egg is totipotent, meaning that its potential is total. In the first hours after fertilization, this cell divides into identical totipotent cells. (Figure I) This means that either one of these cells, if placed into a woman's uterus, has the potential to develop into a fetus. In fact, identical twins develop when two totipotent cells separate and develop into two individual, genetically identical human beings. Approximately four days after fertilization and after several cycles of cell division, these totipotent cells begin to specialize, forming a hollow sphere of cells, called a blastocyst. The blastocyst has an outer layer of cells; inside the hollow sphere is a cluster of cells called the inner cell mass. Figure 1. Cell development. The outer layer of cells goes on to form the placenta and other supporting tissues needed for fetal development in the uterus. The inner cell mass cells goes on to form virtually all of the tissues of the human body. Although the inner cell mass cells can form virtually every type of cell found in the human body, they cannot form an organism because they are unable to give rise to the placenta and supporting tissues necessary for development in the human uterus. These inner cell mass cells are pluripotent — they can give rise to many types of cells but not all types of cells necessary for fetal development. The pluripotent stem cells undergo further specialization into stem cells that are committed to give rise to cells that have a particular function. Examples of this include blood stem cells which give rise to red blood cells, white blood cells and platelets; and skin stem cells that give rise to the various types of skin cells. These more specialized stem cells are called multipotent.

5. Genetic research and disease resistence:

   A crucial component of an immune response is the ability to specifically recognize the pathogen. Three distinct families of immune system proteins are involved—antibodies produced by B cells, T cell receptors (TCR) and major histocompatibility complex (MHC) molecules—with each approaching the problem of recognition in a slightly different way. The genes coding for antibodies and TCRs have a large number of variable gene segments that can recognize an enormous variety of potential pathogen molecules. Binding of an antigen to a particular B cell results in its differentiation and expansion into a group of identical cells that produce a specific antibody that recognizes the antigen. Recognition of pathogen antigen by a particular T cell results in its activation and expansion into a group of pathogen-specific T cells. By contrast, the same MHC molecules are expressed throughout the immune system. Each MHC molecule binds short fragments of pathogen antigens; these MHC-peptide complexes are then transported to the cell surface where they can interact with pathogen specific receptors on T cells. The immune system has evolved two ways to improve the range of antigens that can be recognized by the MHC. MHC genes have been duplicated many times during evolution, and each individual has at least two copies of each MHC gene. MHC genes are highly polymorphic and vary between individuals to a degree not seen in any other gene family. Hundreds of alleles of the human MHC (HLA) genes have been documented. Thus, an individual is unlikely to inherit the same MHC allele from both parents and so has double the effective number of MHC molecules with which to recognize pathogens. The large number of MHC alleles within the population as a whole makes it unlikely that a pathogen will evade detection by a significant proportion of the population, substantially reducing the risk of epidemics.

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