Which of the following comes closest to your view? no genetic engineering whatsoever should be performed on humans.

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1 Which of the following comes closest to your view? GREEN: BLUE: RED: YELLOW: no genetic engineering whatsoever should be performed on humans. gene therapy is OK, but nothing else. I m OK with gene therapy and cloning to produce stem cells, but not reproductive cloning. all of these technologies are OK in principle, as long as they are regulated appropriately. Transgenic animals Traditional breeding methods have been very successful at improving desired traits in livestock, such as milk yield, wool characteristics, rate of weight gain, egg-laying frequency. However, this is slow and inefficient. Also, it is difficult to develop breeding lines with multiple good traits while avoiding bad traits (genetic diseases, etc.) How can we insert specific genes into animals and propagate them from generation to generation? (1) Transfer of genes into the mammalian genome. (2a) Create breeding lines containing these genes or (2b) Create genetically identical animals (cloning). 1

2 How to make a transgenic mouse Transgenic technology was developed and perfected in the laboratory mouse. Hundreds of different genes have been introduced into various mouse strains. These lines have contributed to understanding of many biological phenomena including genetic diseases. There are three methods of trangenesis in mice: (1) use a virus to inject desired genes into harvested embryos before implantation in a foster mother. (2) microinjection of DNA into a fertilized egg followed by implantation in a foster mother. (This is currently the most common method.) These two methods have the disadvantage that only a small number of the progeny will contain the transgene; i.e. selection must be performed after their birth. The final method involves stem cells Stem cells are pluripotent; they can develop into a number of different types of differentiated cells. In mice, pluripotent embryonic stem cells can be maintained indefinitely in cell culture. This means that standard genetic engineering methods can be used to insert genes into these cultured stem cells. The cells that take up the gene can be selected and grown. Finally, these cells can be inserted into developing embryos and implanted into foster mothers. This method is particularly powerful because it permits the use of the full arsenal of genetic engineering techniques prior to implantation. Unfortunately, immortal pluripotent embryonic stem cells like those of the mouse have not yet been discovered for other mammals. 2

3 Applications of transgenic mice Models for human diseases; e.g. Alzheimer disease. Alzheimer disease is a degenerative brain disorder characterized by the progressive loss of abstract thinking and memory. Dense aggregates of proteins (called plaques and amyloid bodies ) are found in the brains of Alzheimer victims. The principal component of these aggregates is beta-amyloid protein. Families with a high incidence of Alzheimer disease are known to have mutations in the gene that codes for this protein. It is impossible to study the physical progression of the disease in humans while they are alive. Transgenic mice are created with the mutated amyloid protein gene. These mice display many Alheimer disease-like symptoms, including amyloid plaques, death of neuron cells, and memory defects. These mice are used to study the progression of the disease and the effectiveness of possible treatments. Transgenic cattle, sheep, goats, and pigs Transgenesis uses a variation of the microinjection method developed for mice. It has been demonstrated to be possible, though currently quite inefficient (but improving rapidly). Increasing livestock value will involve: modifying the constituents of milk to increase cheese production hereditary resistance to bacterial, viral, and parasitic diseases Use as bioreactors: transgenic sheep and goats are created that secrete human proteins in their milk. longer term prospects include production of a human blood substitute and organs for implantation. Antigens that are involved in organ rejection can be replaced with the human version. 3

4 Future prospects: transgenic humans? In a variant of gene therapy, one can imagine correcting defective genes (or selectively modifying certain genes) of embryonic cells before implantation. This issue has not been widely discussed but may be much more significant than issues surrounding cloning. It would allow many couples to have children without debilitating genetic diseases. However, some people are concerned that this would lead to eugenics. Of course, we should assume that any modifications would be voluntary, not coerced, and uncommon because of the expense. Is this the greatest danger facing humans in the 21st century? Or is it just the usual rhetoric about people playing God? Cloning of mammals Nuclear transfer: (1) The nucleus (containing all the DNA) is removed from a oocyte. (2) The DNA from a donor cell is inserted into the oocyte. (3) The oocyte is implanted into a host mother and if the transfer was successful, develops to term. Success rates are low but improving rapidly. 1999: 1 in 500; 2001: 1 in 20 (for cattle) It was traditionally believed that this could work only if the transferred nucleus was taken from a pluripotent cell, like a mouse embryonic stem cell. In 1997, successful nuclear transfer was demonstrated from a differentiated cell taken from an adult mammal. Dolly was cloned by nuclear transfer of a mammary cell from an adult sheep. It has since been duplicated using cows, goats, pigs, cats, monkeys, etc. and no longer seems to be specific to any particular species. It would seem that cloning humans is inevitable as it is essentially a straightforward outgrowth of previous cloning research. 4

5 Commercially-available cattle-cloning services Enucleation Chromosomes of each egg are drawn into a needle. A pipette holds the egg still. After Enucleation Chromosomes are removed, all that remains inside the zona pellucida is cytoplasm. Transfer A skin cell, or fibroblast, from the animal to be cloned is transferred underneath the zona pellucida, where it remains separate from the egg cytoplasm. Fusion Each unit is exposed to an electric shock that fuses the skin cell with the egg cytoplasm. The skin cell s nucleus, with its genes, enters the egg cytoplasm. Embryo Seven days later the CyCloned embryo is ready for transfer into a recipient cow. Cyagra is a subsidiary of Advanced Cell Technology, Inc. Zita CyCLONES Genesis Z and Cyagra Z Cyagra CyCloned the legendary Holstein cow, Con-Acres HS Zita 5

6 Scientists clone 'carbon copy' cat (Last Updated Fri, 15 Feb 2002) COLLEGE STATION, TEX. - Scientists in Texas have cloned a female calico kitten, named "Cc:", believed to be the first pet successfully cloned. Cc: (copy cat) with foster mother The cat was cloned at Texas A&M University as part of the $3.7-million "Missyplicity Project," which is attempting to clone Missy, a mixedbreed dog, for her wealthy owners. Endangered species cloning Inter-species Nuclear Transfer". The egg cell is provided by a related (usually domestic) species, and the pregnancy is carried in an animal other than the endangered animal. This technology could be used to preserve endangered species. Is it useful? Adult Guar Noah, the baby Guar 'Bessie', the pregnant cow carrying the gaur. 6

7 Therapeutic cloning Stem cells are able to form virtually every cell type in the body. Therefore, they are ideal gene therapy delivery vectors and a means to produce artificial tissues and organs. This technology has unusually broad applications in medicine. For instance, neurons for the treatment of Parkinson s disease and spinal cord injury, heart muscle cells for heart failure, cartilage for arthritis, pancreatic cells for diabetes, etc. To solve the compatibility problem, stem cells identical to the patient s cells must be used create stem cells containing the patient s DNA. Rejection-free transplants! Culturing stem cells ~12 days ~100 cells stem cells This example show a fertilized oocyte as the starting point. There are other ways to start the process. 7

8 How are stem cells created in vitro Trick a cell into starting the developmental process. Somatic Cell Nuclear Transfer: A patient s body cell is combined with an egg cell that has its DNA removed. The body cell s DNA is reprogrammed back to an embryonic state, and totipotent stem cells are produced identical to the patient. Successful in numerous organisms. Induced Parthenogenesis: An oocyte is directly activated without the removal of its DNA to begin development on its own. Successful in monkeys! Ooplasmic Transfer: The reverse of nuclear transfer; the cytoplasm of an oocyte is transferred into the body cell of a patient, transforming the patient s cell into a primitive stem cell. Still in development. Ultimately, other methods will be developed; some without oocytes. But perhaps not in the U.S. Cloning human organisms Eventually, embryonic cloning will become very efficient and successful; i.e. there will be little risk of genetic or other defects. This seems far away now, but given the extraordinary pace of this research we must assume it will happen. At that point, will it be reasonable to implant the embryos into foster mothers and bring them to term? Is there an inherent problem with creating delayed twins? Forget silly sci-fi ideas about mass production or loss of humanity. These would be human individuals like any others. Test-tube babies are born every day (IVF). Twins are born every day. Are so many people against it because it s wrong, or because it s new? Rationally evaluate your gut response. 8