A Cross-Cultural Introduction to Bioethics 98




  C1. Genetics, DNA and Mutations

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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                              12...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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A Cross-Cultural Introduction to Bioethics                                                                                ...
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  1. 1. A Cross-Cultural Introduction to Bioethics 98 C1. Genetics, DNA and Mutations Chapter objectives There are numerous ethical issues raised by genetic technology, so a background knowledge of DNA and genetics is needed to discuss the issues. This chapter aims to introduce: 1. Basics of genetics that will be useful for other chapters that discuss the ethical and social issues. 2. What is mutation and how it can cause genetic disease. C1.1. Why do humans make humans, and birds make birds? Organisms do not pass their replica to the next generation but rather genetic material containing information needed to construct a progeny (offspring). In almost all organisms DNA is the genetic material, except for some viruses where it is RNA instead. The genetic constitution of an organism is called its genotype. Interaction of this genetic constitution with the environment results in the physical appearance and other characteristics of an organism which is called its phenotype. DNA works as a database or store of information needed to make an organism. It exists in the form of sequence of four nucleic acids A (adenine) T (thymine) G (guanine) and C (cytosine). When two strands of DNA are together, A binds with T and G binds with C, and these are called base pairs. There are approximately 3 billion base pairs in the human DNA. Genes are coding regions of the DNA that carry necessary information needed to make proteins, which are structures present and operating in the cells and organs. Genes are passed from one generation to the next during reproduction and are called the units of heredity. Variations in the sequence of DNA make each organism different. Genes express and function differently in all species, which makes each species and even each organism unique. Although almost all organisms have DNA (and a few viruses have their genetic information encoded as RNA), the expression of genes determine what we look like in general. Several genes get © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  2. 2. 99 A Cross-Cultural Introduction to Bioethics switched on or switched off during development and determine our phenotype. Environmental interactions also can determine diseases and behaviour. `````The genetic code of all living organisms is made up of DNA. Q1. Think about the closest organisms that are similar to human beings? Q2. What do you think if all organisms look alike? Q3. How many genetic diseases do you know? How many mutations do you have? How many fatal recessive alleles do you carry in your genome? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  3. 3. A Cross-Cultural Introduction to Bioethics 100 C1.2. Mechanism of genetic diseases and mutations Every person has a different genetic sequence except for identical twins. The genes are made of DNA. DNA is a long chain of units, called bases, and there are only four kinds of base (ATCG). Each position of the DNA can be one of the four bases, and the genetic sequence is the order of these bases. In the same way the sequence of this sentence determines what we understand in reading it, the sequence of DNA determines what happens in living organisms. There are only four possible characters for each position, but even a short sequence of 20 positions could have many possible combinations of sequence. DNA is a long chain of these units, which forms a spiral geometrical structure called a double helix. Functional lengths of DNA are called genes. Each gene may be involved in defining one particular function or character at the phenotypic level. There are many new genes discovered every week. Our genes are in long linear strings, called chromosomes. Humans possess 23 different pairs of chromosomes, a total of 46. While every human has the same set of chromosomes and thus types of genes in the same order, each gene has variant types which are called alleles. Alleles differ in their exact sequence of DNA but they should generally perform the same function. We can have many different alleles, for example there are at least 46 distinct alleles of the gene phenylalanine hydroxylase (e.g., a mutated allele of this gene is responsible for the disease PKU). There are mutations found in each of these alleles, which would make total genetic screening for PKU impracticable, but a simple cheap enzyme test can be performed. Mutations are changes in the nucleotide base sequence, and are quite common. Mutations can be caused by random chance, by chemicals or radiation, and most commonly are caused by reactive chemicals (free radicals) formed in the ordinary process of metabolism. Specific mutations are often seen as a response to ultraviolet (UV) light or smoking. The DNA repair enzymes can repair most of these, others may escape repair and can result in abnormalities, such as cancer. If the mutation occurs in the zygote, or reproductive (germ) cells, the new offspring may carry the mutation. Somatic mutations play a role in the development of most cancers, being steps in the process. Only some mutations actually cause harm, others may make no harm (see Fig. 1). This complex system is in delicate balance, and it only requires a defect in a single gene to disrupt this balance, the effect sometimes being lethal. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  4. 4. 101 A Cross-Cultural Introduction to Bioethics Figure 1: Mutations alter Amino Acid Sequences The original and the mutated DNA sequences may give rise to the same amino acid, a different amino acid, or stop translation. A frameshift mutation completely alters the amino acid sequence resulting in a nonsense message. DNA Sequence Protein Sequence Original AACTAATTGCGTA Leu-Ile-Asp-Ala- Neutral Mutation AACTAGTTGCGTA Leu-Ile-Asp-Ala- Single amino acid change AACTACTTGCGTA Leu-Met-Asp-Ala- Deletion, frameshift AACT/ATTGCGTA Leu-Ile-Thr-His- Insertion, frameshift AACTAGATTGCGTA Leu-Ile-STOP The cause of many genetic diseases is a simple nucleotide substitution, which occurs at a low frequency during the duplication of DNA. The effect of this nucleotide alteration is summarised in Fig 1. The effect does not always depend on the size of the deletion, but more on whether the resulting sequence has shifted in the reading frame for protein translation. This is summarised in Fig. 2. For example, in patients with muscular dystrophy, part of a gene for a protein dystrophin is deleted. The severity of the disease depends on whether it is out of frame, rather than how much is missing. As long as some type of protein can be made the muscle cells may still be able to function. Figure 2: Effect of frameshift mutation Original THIS LINE CAN BE READ WELL Single letter deletion (frameshift) THIS LINC ANB ER EADW ELL Whole word deletion (not a frameshift) © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  5. 5. A Cross-Cultural Introduction to Bioethics 102 THIS LINE BE READ WELL There are also more major mutations, where large fragments of DNA can be translocated to a different chromosome. Abnormal chromosome numbers can also occur, so instead of two copies there may be three copies. Because this alters the number of alleles of genes for certain proteins, this can have major affects, usually resulting in death. Trisomy 21, where there are three copies of chromosome number 21 results in Down's syndrome, and is an example where death may not necessarily be the result. In most other chromosome trisomies, death occurs during fetal growth, and/or as a result of spontaneous abortion. Often only one of each pair of alleles of each gene is needed for normal function. Some of the alleles may be so different in their sequence from normal that the protein or enzyme they produce is nonfunctional. If this is the case then the individual will use the other functional allele of the pair and this will normally allow a completely normal life or phenotype. Sometimes one of the alleles produces an abnormal but functional product; again the individual will probably live normally. But if the individual possesses two nonfunctional, or misfunctional alleles for any gene then the effect will be a genetic disease. Normally the defective allele is not used if there is a normal, functional alternative allele, and the allele would be called recessive because of this. A recessive allele/gene is therefore one which does not get used to create the phenotype. The allele which is used is called the dominant allele/gene. People may carry a recessive disease-causing allele without it having any effect on them, but it is possible that it will be passed on to their offspring. In some cases the defective allele is dominant which means even an individual with one normal and one defective gene will suffer from the disease. Dominant and X-linked mutations often cause severe disease and interfere with reproduction so would not last many generations. Recessive mutations have the greatest chance of being maintained in the population, no mutations would be eliminated in the first generation, as each individual would only be a carrier, and if there is only one copy, then there is no effect. They would be present for generations, for example, the most common mutation in cystic fibrosis is thought to have originated about 50,000 years ago. Genetic disease is not usually lethal and some abnormalities have little effect. About 3-4% of children suffer from some type of genetic disease at birth. Every human possesses a specific genotype, consisting of many units called genes; each gene directs the manufacture in our body of a specific component, these components are usually proteins of which the most important class for genetic studies are enzymes. Every person has new mutations, and carry © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  6. 6. 103 A Cross-Cultural Introduction to Bioethics alleles which could cause disease. We all carry about twenty recessive alleles for lethal characteristics, but because these occur at low frequency the incidence of a child being born with two recessive alleles is low. Some mutations are found in the reproductive cells (ova and sperm) and others in the body (somatic) cells. Both types of mutation have the potential to cause cancer. C1.3. Genetic screening DNA is normally found in double-stranded form (the double helix). The four bases are given the symbols, A, T, G, and C. The base A binds with T, and the base G binds with C, between these long chains, as is shown below: ---ATTCCGAAGCTGACTGA--- parent chain ---TAAGGCTTCGACTGACT--- complementary Genetic screening involves the use of this complementary binding. A sample of DNA is taken from a cell, and then the DNA is split into single chains. The bases in this single-stranded DNA will bind to the pairing bases. To make it easier to test, this single- stranded DNA may be fixed to a plastic filter. We can test for the presence of a certain sequence in this fixed DNA by adding a solution of single-stranded probe DNA, a short sequence of synthetically made DNA with a label on it, like a fluorescent dye. After mixing the probe with the sample, the probe that is not bound to the complementary sequence is washed away. If there are copies of the sequence in the sample, we will be able to see the probe when we hold the filter under ultraviolet light, because the probe is fluorescent. If there is no complementary sequence in the sample to the probe, then we will not see any fluorescence. In this way, many samples can be tested, with many probes, and this is known as genetic screening. We screen for the presence or absence of particular DNA sequences that represent different genes. This screening can be used to detect a mutation, for example to tell that a fetus has a mutation that will cause a genetic disease (prenatal diagnosis). It can also be used to detect which types of bacteria may be present in a food sample, or for medical diagnosis of a patient. Information about whether an individual has a particular DNA sequence and gene can be very powerful, especially in the diagnosis of genetic disease. There are many ethical and legal issues that result from this technology, as discussed in following chapters on genetic privacy and information. For example, presymptomatic screening means testing for a late- © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  7. 7. A Cross-Cultural Introduction to Bioethics 104 onset genetic disease, like Huntington's disease, before the person is sick. Such predictive power may require psychological counseling. It is very important that privacy is respected, because the information in a person's genes identifies risk factors for disease that medical insurance companies and employers could use to discriminate against people. There are already cases of discrimination against individuals after genetic testing in North America. Many genetic diseases (such as diabetes or cancer) are caused by the effects of multiple genes, and the relationship between the environment and genes. Genetic susceptibility means that a particular gene is only one determinant for the development of a complex disorder. For example to have an allele called Apo E4 (that about 10% of Caucasians and Asians have) increases the risk of developing Alzheimer's disease, and confers a very strong susceptibility at younger age if you have two alleles. Alternatively, another allele for this gene, Apo E2, seems to be protective against Alzheimer's. Q4. Is there any advantage to having presymptomatic screening for Alzheimer's disease when you are 20 years old? What about when you are 60 years old? Q5. If you check on the Internet for keywords like “gene array” or “gene test”, you can find many examples of genetic tests. Find some examples and write about the advantages and disadvantages of genetic screening. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  8. 8. 105 A Cross-Cultural Introduction to Bioethics C2. Ethics of Genetic Engineering Chapter objectives. Genetic engineering has been a catalyst for discussion of ethical issues related to the modification of nature, and has been politically contentious because of the economic importance of the food industry. This chapter aims to introduce: 1. Basics of genetic engineering. 2. Examples of genetically modified organisms (GMOs) and the purposes for which they are made. 3. Ethical issues of genetic engineering. C2.1. What are genetic engineering and GMOs? With many years of research, scientists have now discovered to some extent which genes do what functions in building organisms. With the help of this knowledge and new developments in scientific technologies, they are able to modify the genetic constitution of organisms for various purposes through genetic engineering. Genetic engineering or genetic modification is an all-inclusive term to cover all laboratory and industrial techniques used to alter the genetic constitution of the organisms by mixing the DNA of different genes and species together. Genetic engineering or genetic modification is the process of recombining DNA. The living organisms made with altered DNA are called Genetically Modified Organisms (GMOs). However, the process is not so simple as precisely cutting out one gene and putting it into . Collaborating authors: Minakshi Bhardwaj, India/U.K. and Darryl Macer, New Zealand © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  9. 9. A Cross-Cultural Introduction to Bioethics 106 another place in the DNA, since genes are surrounded by other sequences in the DNA that determine whether or not a gene from one organism can function in another organism. So a careful study of the GMO is needed to be sure of its safety. Genetic engineering can be used for good causes. However, it can also potentially be misused. Genetic engineering is considered special because often the techniques involve manipulating genes in a way that is not expected to occur ordinarily in nature, allowing characters to be changed, not just between the species but also between kingdoms. Technology is rapid and new ways of manipulation and experimentation are being made. Also it can be applied to the human species (see the Gene therapy chapter). Q1. Can you describe any examples of genetic engineering you have heard of? Q2. Give examples where you think the environment can influence the functions of the genes and the behaviour of organisms. Q3. Find the institutes in your area doing genetic engineering. In which areas are they researching and why? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  10. 10. 107 A Cross-Cultural Introduction to Bioethics C2.2. Examples of genetic engineering in medicine Many human proteins are now being commercially manufactured by the use of gene transfer to microrganisms such as bacteria or yeast, including blood clotting factors, interferons, lymphokines, growth hormone, erythropoietin, insulin and various growth factors, all of which have medical uses. One of the most common proteins in use is human insulin for diabetics, which has been licensed for many countries to use since 1982. Recombinant DNA techniques are also being used to produce human vaccines, for example to produce cheap, easily stored vaccines against major childhood diseases. The logistics of the world-wide immunisation programmes are influenced more by transport, storage and delivery than production. Edible vaccines have also been made as foods, such as hepatitis B vaccine in lettuce or banana (or Plantain), which may avoid the need for medical staff to administer the vaccine, and make the plants cheap enough for third world countries. The degree of expression is not yet high enough for effective use, but is being improved. A genetically engineered vaccine against cattle ticks is being mass produced in Australia, that should help control tick infestation. The tick is an external parasite, but ingests blood, and the vaccine is a modified version of a tick protein from the gut cells, which produces an immune response in the cattle which in turn prevents reproduction of the tick. Modified proteins can also be made, using genetic engineering to alter the catalytic properties of natural enzymes, a process known as protein engineering. Many pharmaceutical products can potentially be made. The medical importance of these recombinant DNA protein products is growing, and the availability of these products makes therapies for a lot of previously untreated or uncured diseases possible. Already there are successful attempts to transfer human genes which incorporate useful proteins into sheep and cows milk, so that they produce, for instance, the blood clotting agent factor IX to treat hemophilia or alpha-1-antitrypsin to treat cystic fibrosis and other lung conditions, also naturally occurring polyclonal antibodies for which at present there are only human donors. Genetic engineering in medicine has been long researched for transplantation purposes, for example, to make organs or body parts like valves for the heart from pigs. There are still safety concerns about large organ transfer from other species (xenotransplants). The most controversial form of genetic engineering in medicine is the use of cloning technology to create organs for transplantation purposes so that they are immunologically compatible. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  11. 11. A Cross-Cultural Introduction to Bioethics 108 Q4. Do you know anyone who has diabetes? If you had a type of diabetes that could be treated by a daily injection of human insulin made by genetic engineering what sorts of side effects might happen from the treatment? Q5. What do you think of genetically engineered vaccines taken through food rather than by injections? Q6. Should we use cloning for organ transplantation? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  12. 12. 109 A Cross-Cultural Introduction to Bioethics C2.3. Environmental use of GMOs Bioremediation is a natural process occurring very slowly in which the bacteria and other micro-organisms breakdown oil into other harmless molecules. Oil spills and oil in waste discharged into the sea from refineries, factories or shipping contain poisonous compounds that are dangerous to the welfare of all living beings, including plants and animals. With environmental pollution on the increase, scientists are developing genetically modified bacteria that can effectively and rapidly digest oil and that are well suited to particular environmental conditions. Others are used to remove algae from ponds and lakes, or to manufacture useful chemicals such as enzymes for plants or to provide renewable resources to make industrial chemicals from. GMOs for environmental clean up have been used in various parts of the world. Not many ethical concerns have been raised against this purpose. However, what is interesting is that natural genetic engineering done by gene exchange between bacteria in the soil or water makes many different bacteria selected to use toxins for their energy source, and these bacteria are better suited to local environments. So usually by adding fertiliser to a polluted area, the already existing bacteria will be able to grow well and clean up the pollution instead of having to introduce new ones. There is still more research needed, but it shows that in nature genes exchange between different organisms, especially rapidly in microorganisms (against the general rule of inheritance discussed in section C1.1). Q7. What kinds of genetic changes to organisms do you think would be helpful or harmful? Q8. What kinds of genetic and non-genetic technologies and methods are alternatives which may be used to improve environmental conditions? C2.4. Ethical Concerns over Genetic Engineering © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  13. 13. A Cross-Cultural Introduction to Bioethics 110 Given that the technology is new, has immense potential, is rapidly developing, and can be applied to all living beings, it can be used for beneficial purposes but there are also risks. It is a sophisticated technology and needs developed laboratory facilities and particular environmental conditions that require investment. Many kinds of GMOs are developed for environmental purposes and for health and medicine. Genetic engineering has been particularly successfully used and applied in food and agriculture to produce genetically modified foods (See a separate chapter C3). Because genetic engineering is still considered a new technology, some doubts, fears, concerns have been raised. Let us consider extrinsic ethical concerns and intrinsic ethical concerns. a) Extrinsic concerns are based on doubts about the technology, its potentiality, newness and applicability to all life forms. There are fears of human misuse of technology, for example for biowarfare or eugenics. There are fears of environmental damage to other organisms or ecosystems. The people in favour of technology think that genetic modification provides a great opportunity for feeding people or treating sick persons with new medical products. The novelty of the technology is one of the reasons people think there are many ethical issues, as they have concerns about health impacts and other potential dangers. In addition, there are concerns about the centralization of economic control over living things, such as the patenting of life. b) Intrinsic concerns are based on how people view life, nature, religion, their personal emotions and values. There is a feeling that mixing up genes in the organisms for our use is "Playing God" and human beings should not intervene in God’s realm. Crossing natural species boundaries is creation of new life forms and inventing a new world through technology. Genetic engineering disrupts the beauty, integrity, balance of nature and might harm life. However, at the same time we can say that concrete cities and high tech medicines involves playing God, and agriculture was started by disrupting nature. Also hybrid plants and animals like mules are cross-species organisms which have existed for many years. In fact mules have been cloned and can reproduce in that way! There are fears that it could be misused for cloning human beings or making genetically enhanced "designer babies", so that parents can select, chose and improve the characteristics of their babies like blue eyes, fair skin, tall, boy or girl, etc. However, the success rate of cloning is very low and its applications are still in very early stages of research. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  14. 14. 111 A Cross-Cultural Introduction to Bioethics (See later chapters on human gene therapy and on cloning) Q9. Please write down your own ethical concerns about genetic engineering. Q10. What is “playing God”? How much do you interfere with nature in your daily life? Q11. Is it good for society to be cautious in the use of new technology? Can you think of existing technologies which are harmful? C2.5. Environmental Risks of GMOs During 1973-1976 there was a voluntary moratorium imposed by scientists on the practise of introducing foreign DNA into bacteria, following an International Conference in Asilomar, California. The fears were that moving genes widely could have bad consequences, for instance it could cause the spreading in the microbial world of antibiotic resistance, or toxin formation; or that genetic determinants for tumour formation or human infectious diseases would be transferred to bacterial populations, which could then infect human beings. After discussions there was a declaration and development of levels of risk for different types of organisms, for example, so that dangerous pathogens would only be used in the highest level of biosecurity containment. Both physical and biological containment are used when we do not know the environmental or health safety of a novel organism. "Biological" containment advocated the use of "crippled" host cells and vectors, such that these would have no success in colonising any environment outside that of the contained laboratory even if they managed to escape from it (e.g. E. coli K12). Since the initial categories of physical containment were decided upon there has been widespread experience gained in the practise of these experiments, which has resulted in a decrease in the assessed hazards and thus the type of containment judged necessary. The principle of biological containment is still used for most laboratory experiments, especially when dealing with human genes and/or tumour-promoting agents. Physical containment is not so strict, but is still maintained for work on tumour or disease- promoting agents. Q12. If you read the book or saw the movie Jurassic Park, can you describe © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  15. 15. A Cross-Cultural Introduction to Bioethics 112 what methods of biological containment and physical containment were used to control the genetically rebuilt dinosaurs? (See also the Movie Guide) Before the appearance of genetically modified organisms (GMOs) there have been harmful effects from some of the accidental releases of organisms from laboratories. In 1958 tobacco blue mould (Peronospora tabacina) was brought into the UK for a research institute. In that year the mould spread to four other institutes, including one in the Netherlands, and to a commercial tobacco crop in England. In the following year the disease appeared in the tobacco fields of Belgium and the Netherlands, from where it spread quickly across the rest of Europe (advancing in Germany at the speed of 5-20 km per week). After several years of crop breeding resistance was increased, but it is a powerful example of the risks of accidental release of new organisms. There are many more common examples of ill effects from the introduction of novel species into Australasia, for example rabbits and cane toads. The deliberate environmental introduction of any new organism, including GMOs, should be only undertaken within a framework that maintains appropriate safeguards for the protection of the environment and human health. Natural habitats already contain their own indigenous populations of organisms, organised in a delicate web of nature, which needs to be maintained. Recent introduction of biological pest control agents has been more successful due to better ecological assessment. We should also note that most food crops and ornamental plants are introduced species, although they are also essential for the economic prosperity of most regions of the world. The environmental release of genetically modified organisms (GMOs) is now assessed by regulatory authorities and trials are common in many countries. Only small scale agriculture can be conducted in semi-closed environmental systems, though some important products used today are produced in that way, such as eggs from battery farming of chickens (which raises ethical questions of farming methods). There have been many field trials since 1984 when Canadians field tested a transgenic plant. There is public concern about the free release of recombinant organisms into the environment, and the degree of care required depends on the potential risk to the ecological balance and humans. Scientific methods and experiments are being used to look at the risks, which include gene transfer and the cross- breeding resulting in new weeds. These are sometimes called “superweeds”, if they include © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  16. 16. 113 A Cross-Cultural Introduction to Bioethics genes for tolerance to herbicides. International transport of GMOs is regulated by an international Convention, the Cartegena Protocol to the Convention on Biological Diversity, which entered force on 11 September 2003. Q13. Can you think of any species that were introduced by human beings into your country? Do they have positive and/or negative effects on your society, economy and environment? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  17. 17. A Cross-Cultural Introduction to Bioethics 114 C3. Genetically Modified Foods Chapter objectives. Since 1995 people in the U.S.A have routinely eaten food made from plants that have been modified by genetic engineering. The economic importance of the food industry is one of the reasons why some other countries have placed limits on import of genetically modified (GM) food, as well as health concerns to the public. This chapter aims to introduce: 1. Issues of genetically modified food. 2. Ethical issues of labeling genetically modified food. C3.1. Genetic engineering and Food Genetic engineering or genetic modification alters the genetic constitution of organisms by mixing the DNA of different genes and species together. The living organisms made with altered DNA are called Genetically Modified Organisms (GMOs). Genetic engineering is considered special because often the techniques involves . Collaborating author: Minakshi Bhardwaj, India/U.K. and Darryl Macer, New Zealand © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  18. 18. 115 A Cross-Cultural Introduction to Bioethics manipulating genes in a way that is not expected to occur ordinarily in nature, that characters can be changed between species. Many kinds of GMOs have been developed for environmental purposes and for health and medicine. Genetic engineering has been particularly successfully used and applied in food and agriculture to produce genetically modified (GM) foods. Use of genetic engineering technologies in food and agriculture to produce GM food has been very controversial. Genetic engineering has been used to produce transgenic plants that carry several enhanced characteristics by inserting genes from various organisms, for example, plants with increased yield, disease resistance, and pest resistance with inserted Bacillus thuriengensis (Bt) insecticidal protein genes which selectively kill pests that eat crops. There have also been fruits and vegetables modified for long term storage or delayed ripening that remain fresh for a long time, which is also useful during transportation to the market. Over 15 countries of the world used GM crops for general food production by 2004. C3.2. Better Foods? In 1996 a new tomato variety was sold in the U.S.A. made by a technology involving use of antisense RNA sequences to bind to the mRNAs of undesired proteins. The concentration of an enzyme (poly-galacturonase), which is produced by ripening tomatoes causing softening of the tomato, was reduced by up to 99%. This enzyme degrades the cell wall in the tomato, so its absence leaves the fruit firmer longer. These tomatoes have been developed to improve shelf life (about 300% longer) and taste since growers can leave the tomatoes on the plant longer. It is also useful to transport to the market, especially in developing tropical countries where it is very hot. The so-called tasty tomato, Flavr Savr (Flavour Savour), was not however very commercially successful when sold in supermarkets in the USA. The second wave of GM plants includes those with high nutritional content and improved food quality like golden rice, or plants that can tolerate high salt levels in the land or are modified so that they can grow in harsh conditions like drought. Some GM food such as golden rice or bananas with vaccines are being developed for health purposes. Golden rice © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  19. 19. A Cross-Cultural Introduction to Bioethics 116 has increased levels of beta-carotene, considered to be especially beneficial for people with vitamin A deficiency. Q1. Are there any GM foods in your country? Q2. Which food in the supermarket is not modified in some way? Q3. What other benefits can you think of from tomatoes which do not go soft quickly? What other agricultural uses of genetic engineering do you know? Q4. Do you think golden rice is a "good" GM food? What other information do you need to make a judgment? C3.3. Ethical issues of GM Food Some people think that products made from GMOs are unnatural. Some call them as Franken-foods. We need to think about whether they are different from existing food varieties. It is not possible for the consumer to differentiate GM food from other conventionally grown foods since both look the same, may even taste the same, unless it is mentioned on the labels of the packets. It is difficult to say that the food is unsafe given that in some parts of the world, like in the USA, people have been eating GM food for a decade. In other parts of the world, especially in Europe, many people are not willing to accept GM food because of fears of health risks and other ethical concerns. We can find people with allergies to many foods, and there will always be some people who have an allergy. That is another reason why people may need to know what is in the food. In the modern supermarket however, most foods are processed containing some compounds from many different plants, especially soybeans. In the USA, the Food and Drug Administration (FDA) has said it is not necessary to label food containing products of genetic engineering. This is against the views of many public groups who argue that it is best to have more information available for the consumer and that food origin is of interest to consumers. In Europe or Saudi Arabia for example, any food with more than 1% from each GMO must be labeled, and in Australia, Japan and New Zealand it is © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  20. 20. 117 A Cross-Cultural Introduction to Bioethics any food with more than 5% from each GMO. As discussed in the chapter on genetic engineering we can consider these types of concerns as extrinsic ethical concerns. The people in favour of technology think that genetic modification provides a great opportunity for solving hunger, food insecurity, and malnutrition in the world since it can be made for all environmental conditions and help in increasing quantity and quality of food. It is these arguments which have led the United Nations Food and Agriculture Organization (FAO) and United Nations Development Program (UNDP) to support the selective applications of genetic engineering for food production. At the same time, there are fears raised about the safety of the food and risks to health since it is considered a new technology and people fear that some genes will be transmitted to them. Many NGOs in the world have also raised the concern that growing genetically modified crops will be harmful for the environment and genetic modification will result in "superweeds". For example, if herbicide resistance genes from canola will flow into weedy relatives to make them resistant to herbicides. Scientific studies are still being conducted to evaluate the actual risks. It is also said that GM crops are unsafe for other organisms that feed on them, for example, some people claimed Bt toxin kills Monarch butterfly larvae. Extensive scientific studies found this was not true, however, these stories are still found on the Internet and in some NGO circles. In general farmers growing Bt crops use less pesticides and less dangerous pesticides than they used to use in "conventional" agriculture. This can be beneficial to the environment, especially if GM can target specific pests more effectively than the broadly toxic pesticides which devastate many non-pest invertebrate groups. There is a fear that GM crops and foods will result in the loss of our biodiversity. Also, since the technology is new and needs lots of investment, it would be unfair to small farmers in poor countries. These are valid concerns and demand scientific investogation. However, the scientific studies have not been conclusive, and there may be benefits in some environments and societies and not in others. There have been contradictory reports both in favour of and against genetic modifications which are confusing people. Q5. Do you think GM food will be an appropriate method for eradicating hunger and malnutrition from the world? How else can we eradicate hunger and malnutrition in an ever increasing global population? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  21. 21. A Cross-Cultural Introduction to Bioethics 118 Q6. What is a safe food? Would you eat GM food? Q7. How much information should be on food labels? Bring some examples to class to discuss. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  22. 22. 119 A Cross-Cultural Introduction to Bioethics C4. Testing for Cancer Gene Susceptibility Chapter objectives. Breast cancer kills more women than it does men, but it is a question that faces all in society. This chapter aims to consider: 1. genetic testing using the example of breast cancer. 2. risks and benefits of genetic testing. 3. limitations of genetic testing. C4.1. Testing for cancer gene susceptibility Genetic testing is based on knowing the genetic code of cells in our bodies. This genetic code, in the form of the chemical DNA, determines everything from hair colour to the way we digest food. Mutations, or changes to the structure of DNA, can make us more susceptible to some diseases or disabilities. Even if you have a mutation, it may not mean you will get the disease, but just that you are more likely to get it. The link between having the mutation and the possibility of getting the disease is not well understood. For example, some genetic mutations interact with factors like a person’s lifestyle or other environmental factors such as chemicals or sunlight. The technology for testing for some mutations is now available. Imagine that a simple blood test could tell you if you have a mutated gene that makes you susceptible to getting cancer. There may be the possibility that you could pass this mutation on to your unborn children. . Collaborating author: Lindsey Conner, New Zealand © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  23. 23. A Cross-Cultural Introduction to Bioethics 120 Genetic testing provides some opportunities to find out about possible health problems that may not happen for many years. Knowing whether you are more susceptible to a disease gives you the opportunity to minimize the risks, for example, making lifestyle changes. Information from genetic testing is powerful knowledge which raises important questions: • Do we want to know what could go wrong with our health in the future? • How accurately does it predict the future? • Who should be informed and when? • Could this knowledge be used against someone? • Should people be told if they do not want to know? Q1. If your sister tests positive for the BRCA1 gene, would you recommend to her that she have her breasts or ovaries removed as a preventative measure? • C4.2. Trash and treasure activity A researcher must dig to find words to help answer the questions (treasure) and toss aside unnecessary sentences, phrases, words, ideas as trash because they do not answer the questions and therefore are unimportant in this context. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  24. 24. 121 A Cross-Cultural Introduction to Bioethics What to do Choose ONE question from the list below and write it on a piece of paper. A. What are the advantages of being screened for the breast cancer gene BRCA1? B. Why do women who are tested need counselling? C. What are the implications for a person who is tested to be positive for the gene? D. What are the implications if the test is negative? 1. Scan the text (C4.3) sentence by sentence to find the answer. Ask “Does this sentence answer the question (A, B, C and D)?” 2. If it does not answer the question, it is trash. Go on to the next sentence. 3. If it does answer the question treasure it by writing down the words or phrase that answers the question. 4. Continue to read the text until you have finished sorting the trash and treasure. Make sure you keep all the treasure as notes. C4.3. BRCA testing Changes to the gene BRCA1 have been linked with breast and ovarian cancer. BRCA1 is a tumour suppressor gene. Tumour suppressors are genes that control cell growth. When enough cells in an area have grown, the tumour suppressors tell the cells to stop growing. When these genes don’t work properly, as in the case of mutated BRCA1 genes, © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  25. 25. A Cross-Cultural Introduction to Bioethics 122 the signal to stop growing is not always given, growth continues out of control, and tumours result. To test for a BRCA1 mutation, a blood sample is taken, and a specific change on chromosome 17q21 is searched for. Only 5% of women with breast cancer are thought to have this particular mutation. Genetic testing can lead to early detection that could help to prolong and save lives. The information could cause havoc if it was misused or misunderstood. When a woman is told that she carries the gene, she has the following options. She could simply monitor her health. In the case of ovarian cancer this may not be enough as often symptoms do not appear until it is too late. She could choose to have a preventative mastectomy (surgery to remove her breasts) or hysterectomy (surgery to remove either just the ovaries or the uterus and the ovaries). Making the decision and having an operation can cause stress. People deal with stress in different ways. Some people become devastated. This may lead to anxiety attacks, depression or even heart disease. Some people, even if they cannot change their future, find information of this sort beneficial.... the more they know, the more their anxiety level goes down. But there are others who cope by avoiding, who would rather stay hopeful and optimistic and not have difficult questions answered. Some people feel they would have more control over their health if they knew they had inherited a defective gene. Some women might choose to have their children early in life and then proceed with a hysterectomy. And others feel they simply could not adjust to a positive test result. This type of testing can have enormous implications on future employment or health and life insurance eligibility. Suppose a person learns that they have a predisposition to cancer; would they be forced to inform their employers and insurers about the test results? Potential employers may hold this information against them and not offer them the job. If insurance companies were given this information, premiums would increase for those at risk and life insurance may be denied. There are also implications should a person test negative, as this result may lead to people feeling that will not get cancer (complacency). A woman might decide not to monitor her health carefully, neglecting the early detection practices such as self- exam © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  26. 26. 123 A Cross-Cultural Introduction to Bioethics and mammography feeling that she is safe from this cancer. Complacency would be especially harmful if the test results are actually a false negative. It is estimated that less than one in ten cases of cancer results from inherited gene mutations. Most cancers are not the result of inherited factors. Even if a mutation in a gene for a particular cancer is inherited, for example the BRCA1 gene for breast cancer, the cancer will not always develop. Also, both men and women without the gene can also develop breast cancer. Discussion Questions Q1. If your sister tests positive for the BRCA1 gene, would you recommend to her that she have her breasts or ovaries removed as a preventative measure? Q2. What information does the article give to help you answer each question? Q3. What additional information do you need? Q4. Is it illegal in your country to use a blood sample for genetic testing even though the sample was taken for another reason? Q5. Write a list of risks and limitations of genetic testing. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  27. 27. A Cross-Cultural Introduction to Bioethics 124 C5. Genetic Privacy and Information Chapter objectives. The issue of genetic privacy has been becoming more important in debates about genetic testing. Genetic information may come from many sources, including a person’s family medical history, a clinical examination or a scientific test. This chapter aims to introduce: 1. What human genetic information is. 2. How we can learn about our genetic information. 3. Privacy concerns raised by that information. C5.1. Genetic information Genes largely determine who we take after in our family, and usually we can see a mixture of our father and mother, and someone new. Human cells have 46 chromosomes, 23 from each parent. Each chromosome is composed of a very large single deoxyribonucleic acid (DNA) molecule. A DNA molecule consists of two strands that wrap around each other in a twisted ladder conformation called a “double helix”. Each ladder rung consists of a pair of chemicals called bases, either A (adenine) and T (thymine) or C (cytosine) and G (guanine). There are over three billion of these base pairs of DNA making up the human genome. Genes are made of DNA. They code the directions for building all of the proteins that make our body function. Except for identical twins, every person has a different genetic sequence. Variation of this sequence, and the responses to environmental factors, accounts for human diversity. There are different types of genetic information. The genotype of a person is all the DNA they have. It provides details, at the fundamental level of DNA or protein sequence. . Collaborating authors: Baoqi Su, China and Darryl Macer, New Zealand © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  28. 28. 125 A Cross-Cultural Introduction to Bioethics Phenotype is the observable outcome in terms of physical characteristics. In many cases the phenotype is a result of the interaction between genotype and environmental factors, for example, our body weight. Information about a person’s physical features and gene- inherited diseases are part of the individual’s genetic information. Q1. What genetic factors determine whether we are man or woman? Q2. Think about what characters are determined by genetics and which are determined by the environment. Q3 Would you like to know your genes? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  29. 29. A Cross-Cultural Introduction to Bioethics 126 C5.2. What does genetic testing tell us? A genetic test is a laboratory analysis of DNA, RNA, or chromosomal abnormalities that cause or are likely to cause a specific disease or condition, for example, Down syndrome. Tests can also analyze proteins or chemicals that are products of particular genes. Different types of genetic testing can be used to identify carriers of genetic disease, screen newborn babies for disease, predict risks of disease, establish clinical diagnoses and determine direct treatment. Prenatal testing of embryos and fetuses is also widely conducted in some countries, while in other countries it is not permitted if it is linked to abortion (see later chapters). Predictive testing estimates the likelihood that a healthy individual with or without a family history of a certain disease might develop that disease. For example, women who carry the mutated BRCA 1 or BRCA 2 (for BReast CAncer) gene are more likely to develop breast cancer and ovarian cancer than other people. Information about a genetic predisposition can be beneficial to individuals. It can make them seek medical advice and receive therapy for the disease at the earlier stage, so that they can try to avoid environmental factors. However, in the case of single-gene diseases like Huntington's Disease (HD), which has no effective treatment and is invariably fatal; some people may choose not to know the result of the tests. Moreover, a great deal of sensitive personal information can be derived from genetic testing with ethical, legal, and social implications (ELSI) for individuals, families and others. Q4. Can you get a genetic test in your country? If yes, for what diseases? Q5. Should genetic testing be performed when no treatment is available? Give reasons for your answers and discuss. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  30. 30. 127 A Cross-Cultural Introduction to Bioethics Q6. Should genetic testing be used for children? Why? At what stage in life would you undergo genetic testing? Q7. What do you think are some ethical, legal and social implications of genetic testing? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  31. 31. A Cross-Cultural Introduction to Bioethics 128 C5.3. Who should know your genetic information? The issue of genetic privacy has been becoming more important in debates about genetic testing. Some genetic information, such as the color of our eyes and hair is easy to see, and cannot be kept secret. But other personal genetic information, such as risk for developing a health disorder late in life, may have a much more private character. People do not expect such information to be disclosed because they feel that this type of information is too personal. Who owns and controls personal genetic information? Who has a right to know the results of a genetic test? The ethical principle of privacy has set limits on who can have access to personal genetic information, and how should it be used. Respect for an individual’s genetic privacy requires us to be sensitive to the special role that genetic identity has come to play in their lives. The effects on a person of being informed that he or she would suffer a genetic disorder can be seriously harmful. It may change their ways of thinking of themselves, and change decisions about matters such as marriage, childbearing, and other lifestyle choices. Moreover, genetic information is not only about an individual, but also involves that individual’s family and the community in which they live. Q8. What does privacy mean to you? What things belong to your definition of personal space? Do you think that privacy is individually or culturally determined? Q9. Does your school have your medical records? Who can access them? If not, where are your medical records located? Q10. Do you have a right to know the results of your aunt’s, cousin’s, brother’s, sister’s, or parent’s genetic test? Why or why not? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  32. 32. 129 A Cross-Cultural Introduction to Bioethics © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  33. 33. A Cross-Cultural Introduction to Bioethics 130 C5.4. Employment and Life Insurance Genetic testing not only has the potential to improve the diagnosis, prevention and treatment of diseases, but it can also reveal details of a person’s current health as well as information about their susceptibility to disease. It also opens up the possibility of identifying a group of people who may be regarded as socially undesirable, perhaps leading to prejudice or discrimination. An important question facing us is to what extent, if any, genetic traits, conditions, or predispositions should provide a basis for determining access to certain social goods, such as employment and insurance. While individuals may be sure about what they do not want employers to know, employers may believe they have a number of reasons why they should know about medical and genetic information likely to affect the health and performance of employees. Employers have a legitimate interest in ensuring that an employee will be able to perform the requirements of the job, especially with regard to safety issues. An employee with a susceptibility to a genetic disorder has the potential to productivity losses and costs associated with the disease. Employers also have the potential legal liability for injuries to employees. (See the movie guide for the film GATTACA, which illustrates how genetic testing does not determine a person’s ability to contribute to a company). The use of genetic information by employers raises a number of ethical issues for workers, such as issues of privacy and discrimination. Employees may also be concerned about discrimination by third parties, such as other employers, if the genetic information is disclosed to them. We should ask whether employers have a right to ask applicants to take a test as a condition of employment. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  34. 34. 131 A Cross-Cultural Introduction to Bioethics Quite apart from the issues of employment, individuals who are found to be at risk for some genetic disorders may find they can get only very expensive life insurance, if they can get any at all. Insurers may attempt to use genetic information as a condition of insurability. This is because certain kinds of genetic information may reveal significant information about a person’s future health. Insurers may ask applicants to disclose genetic information derived from a genetic test or from family medical history. Q11. Are the results of genetic tests different to what people can determine from your family history of disease? Q12. Would you take a genetic test if a family member asked you to? What about if your school asked you? Or an employer or insurer asked you? Who has rights to know the results of your test? Q13. Are individuals entitled to keep exclusive information about their genes? Is an insurance company entitled to know what risk they are taking before insuring an applicant? Q14. For what purposes should other persons ("third parties") use this information? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  35. 35. A Cross-Cultural Introduction to Bioethics 132 C6. The Human Genome Project Chapter objectives The Human Genome Project has been the project to sequence all human DNA and map the genes and DNA sequences that determine genetic variation. There have also been many other species as subjects of their own genome projects, which provides interesting biological information fundamental for understanding how to apply biotechnology to practical use. This chapter aims to introduce: 1. The human genome project. 2. The roles of the International Human Genome Organization. 3. Some examples of other genomes being sequenced. C6.1. The Human Genome Project The Human Genome Project (HGP) aimed to map and sequence all the DNA of human beings, known as the genome (a total of about 2.8 billion linear bases on 23 different chromosomes). There are thought to be about 30,000 genes in human beings, and most of these have been identified. However, the genes comprise only 5-10% of the total DNA in the human genome, the function of the rest of the DNA is unknown. While most genes have been identified, the function of most of them is still to be investigated. The Human Genome Project was conducted by a publicly financed international research effort whose goal was to decipher the human genetic code and to provide these data freely and rapidly to the public. In addition a company called Celera, and several others, also © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  36. 36. 133 A Cross-Cultural Introduction to Bioethics made intensive efforts to sequence the human genome. On June 26, 2000, members of the Human Genome Project announced that they had succeeded in sequencing a "working draft" of the human genome. An article published in the February 15, 2001 issue of the journal Nature outlines the strategies and methodologies used by this group to generate the draft sequence. Sequencing of the human genome represents a scientific milestone, and the data are of immediate use in many important ways. To further understand and use the information coded for in this "human blueprint", several international bodies, including the U.S. National Center for Biotechnology Information (NCBI) provide access to these data worldwide through public Web sites (http://www.ncbi.nlm.nih.gov). The Human Genome Organisation (HUGO) was conceived in late April 1988, at the first meeting on genome mapping and sequencing at Cold Spring Harbor, New York state, USA. For some time, as the genome initiatives got under way in individual nations, the need for an international coordinating scientific body had been under discussion. The HGP was the natural culmination of the history of genetics research. In 1911, Alfred Sturtevant, then an undergraduate researcher in the laboratory of Thomas Hunt Morgan, realized that he could - and had to, in order to manage his data - map the locations of the fruit fly (Drosophila melanogaster) genes whose mutations the Morgan laboratory was tracking over generations. HGP researchers have deciphered the human genome in three major ways: determining the order, or "sequence", of all the bases in our genome's DNA; making maps that show the locations of genes for major sections of all our chromosomes; and producing what are called linkage maps, complex versions of the type originated in early Drosophila research, through which inherited traits (such as those for genetic disease) can be tracked over generations. This ultimate product of the HGP has given the world a resource of detailed information about the structure, organization and function of the complete set of human genes. This information can be thought of as the basic set of inheritable "instructions" for the development and function of a human being. Although the so-called full sequence was completed and published in April 2003, there are still a few portions of the genome that are not accurately sequenced because that DNA is difficult to isolate and prepare for sequencing. Q1. When did you first hear of the Human Genome Project? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  37. 37. A Cross-Cultural Introduction to Bioethics 134 C6.2. The Human Genome Organisation (HUGO) Mission Statement: * to investigate the nature, structure, function and interaction of the genes, genomic elements and genomes of humans and relevant pathogenic and model organisms; * to characterise the nature, distribution and evolution of genetic variation in humans and other relevant organisms; * to study the relationship between genetic variation and the environment in the origins and characteristics of human populations and the causes, diagnoses, treatments and prevention of disease; * to foster the interaction, coordination, and dissemination of information and technology between investigators and the global society in genomics, proteomics, bioinformatics, systems biology, and the clinical sciences by promoting quality education, comprehensive communication, and accurate, comprehensive, and accessible knowledge resources for genes, genomes and disease; and, * to sponsor factually-grounded dialogues on the social, legal, and ethical issues related to genetic and genomic information and championing the regionally-appropriate, ethical utilization of this information for the good of the individual and the society. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  38. 38. 135 A Cross-Cultural Introduction to Bioethics The vast implications to individuals and society of possessing the detailed genetic information made possible by the HGP were recognized from the outset. Another major component of the HGP is devoted to the analysis of the ethical, legal and social implications (ELSI) of our newfound genetic knowledge, and the subsequent development of policy options for public consideration. Up to 5% of the money in some countries is being spent on the educational, ethical, legal and social impact. The HUGO Ethics Committee was made with the following purposes: * to promote discussion and understanding of social, legal and ethical issues as they relate to the conduct of, and the use of knowledge derived from, human genome research. This may encompass consideration of research directions, practices and results, and the issues of human diversity, privacy, and confidentiality, intellectual property rights, patents, and commercialisation, disclosure of genetic information to third parties, the non-medical use of such information, and the medical, legal and social aspects of testing, screening, accessibility, DNA banking, and genetic research; * to act as an interface between the scientific community, policy makers, educators, and the public; * to foster greater public understanding of human variation and complexity; * to collaborate with other international bodies in genetics, health, and society with the goal of disseminating information; * to deliberate about policy issues in order to provide advice to the HUGO Council and to issue statements where appropriate; * to report on its activities at least annually to the HUGO Council: and to act on any other related matter. C6.3. Sequencing of Other Genomes The tools created through the HGP also continue to inform efforts to characterize the entire genomes of over a hundred other organisms important for medicine, agriculture and biological research, such as mice, rats, rice, chimpanzees, fruit flies, flatworms and many bacteria. These efforts support each other, because most organisms have many similar, or "homologous," genes with similar functions. Therefore, identification of the sequence or function of a gene in a model organism has the potential to explain a homologous gene in human beings, or in one of the other model organisms. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  39. 39. A Cross-Cultural Introduction to Bioethics 136 Many genetic techniques have been improved including: * DNA Sequencing * The employment of Restriction Fragment-Length Polymorphisms (RFLP) * Yeast Artificial Chromosomes (YAC) * Bacterial Artificial Chromosomes (BAC) * The Polymerase Chain Reaction (PCR) * Electrophoresis Q2. If you look on the Internet you can find the DNA sequence of many different species. How similar are different species to human beings?Do you know how similar your genome sequence is to another person? Q3. The International Haplotype Mapping (HapMap) project is looking at the variation between human populations. Did you know that between any two people there are about one million DNA base pairs difference, and 85% of the differences are within any so-called race. Therefore the concept of race used in society does not have clear genetic foundations. Q4. Do you think that it is good to map the human genetic lineage through all population and ethnic groups? Should we ask each group whether they want to know the results? How might the information be misused? Q5. Do a web search for the Genographic project and consider whether it is a good project? Would you like to trace your own personal genetic history? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  40. 40. 137 A Cross-Cultural Introduction to Bioethics Footnote Many of the ethical issues of human genetic information and screening are discussed in chapters in this section of the textbook. There have also been two International Declarations issued by UNESCO relating to use of human genetic data (see the text in following chapters). The statements by HUGO ethics committee are on their web-site. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  41. 41. A Cross-Cultural Introduction to Bioethics 138 C7. Eugenics For millennia there have been attempts to improve hereditary qualities through selective breeding. Eugenics can be defined "as any effort to interfere with individuals' procreative choices in order to attain a societal goal". The word means "good breeding" from the Greek names Eugene and Eugenia expressing the notion of "well born" which was a celebration of parents’ belief that their offspring are especially blessed. The term "eugenics" was coined by Sir Francis Galton, an English scientist (1822-1911), based on studies of hereditary and Mendelian genetics. The eugenic idea has been abused in the past; for example, by the Nazis in the 1930s and early 1940s. Some countries have implemented social policies to promote eugenic population selection even today, including immigration policies and reproductive technology, but generally modern eugenics is based on eliminating genetic disorders. Several forms include: Eugenics of normalcy: Policies and programs intended to ensure that each individual has at least a minimum number of normal genes. Negative eugenics: Policies and programs intended to reduce the occurrence of genetically determined disease. Many countries sterilized persons to stop them having children in the twentieth century. Positive eugenics: The achievement of systematic or planned genetic changes to improve individuals or their offspring. This includes selection of healthy genes, and use of gametes from people thought to be superior in intelligence or physical characters. When abused it has been developed into genocide and "ethnic cleansing". Ethnic cleansing is the mass expulsion or extermination of people from a minority ethnic or religious group within a certain area and who, in many instances, had lived in harmony for generations prior to the outbreak of national hostilities. Well publicized examples include ethnic atrocities experienced in the former Yugoslavia. War violates fundamental human decency but is at its worst when actions are taken against civilian populations subjected to atrocities such as rape, assassinations, massacres, torture and ethnic cleansing. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  42. 42. 139 A Cross-Cultural Introduction to Bioethics Q1. What is a bad gene? What is a good gene? Is there any such thing? Q2. How different are other person’s perceptions of bad and good? How much desire could parents have for certain characters, e.g. eye colour, height, obesity, of their children? Q3. What did the Nazi eugenics policy in Germany in the 1930s-1945 lead to? Q4. Does anyone want to have sick children? How much should we try to have children without disease? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  43. 43. A Cross-Cultural Introduction to Bioethics 140 C8. Human Gene Therapy Chapter objectives Gene therapy has been discussed since the 1970s but despite clinical trials since 1990 it has not yet been very successful. It is however a symbolic issue in bioethics, for it is a technology that was discussed prior to its use widely in many societies from the ethical perspective. This chapter aims to: 1. Introduce somatic cell and germ-line gene therapy. 2. Consider the risks and benefits of gene therapy. 3. Investigate the relationship between discussion of ethics and evolution of regulation. 4. Consider human genetic engineering. C8.1. Gene Therapy trials Many genetic diseases may be able to be treated by correcting the defective genes, using gene therapy. Gene therapy is a therapeutic technique in which a functioning gene is inserted into the somatic (body) cells of a patient to correct an inborn genetic error or to provide a new function to the cell. It means the genetic modification of DNA in body cells of an individual patient, directed to alleviating disease in that patient. There have been several hundred human gene therapy clinical trials in many countries (including USA, EU, Canada, China, Japan, New Zealand…), involving over 6000 patients world-wide, for several different diseases including several cancers. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  44. 44. 141 A Cross-Cultural Introduction to Bioethics Genetic engineering is altering the genetic composition of a living organism by technological means based on recombinant DNA technology (see Chapter C2). This can involve altering the gene sequence, or addition, substitution, and/or deletion of DNA. It has contributed to the understanding of genetic diversity which is useful in the conservation of plants, animals and microorganisms. Genetic intervention is a general term for the modification of inheritable characteristics of individuals or populations through various social mechanisms and/or biomedical technologies. What is happiness? Quality of life. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508> Being sick is not much fun!
  45. 45. A Cross-Cultural Introduction to Bioethics 142 Figure 1: Types of Treatment of Human Genetic Disease After conception the genotype may be "normal" (without a genetic disease) or "abnormal" (with a genetic disease). There are several stages at which therapy could occur. Somatic cell therapy can be performed before birth or after. Symptomatic therapy (to treat the symptoms of the disease by diet or medicine for example) usually occurs after birth, but may also occur before birth in some diseases where it is possible and necessary to treat early. The questions of reproduction are more complex, as someone healthy in their life may still have problems with their fertility or pass on a genetic disease to their children. Conception Gene Therapy on Embryo or Fetus Abnormal Genotype Normal Genotype Primary Prevention (e.g. abortion) (Healthy gestation) Early Death Birth Abnormal Genotype Normal Genotype Somatic Cell Gene Therapy Secondary Prevention (e.g. euthanasia) Disease Symptomatic Therapy Health Abnormal Genotype Normal Genotype Germ- line gene therapy Reproduction (See chapter on fertility) Sterilization? Donor gametes? Prenatal diagnosis? "Healthy" children (see chapter on eugenics) What is happiness? Quality of life… © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  46. 46. 143 A Cross-Cultural Introduction to Bioethics Gene transfer refers to the spread of genetic material through natural genetic mechanisms. Little is known about the frequency of genetic exchange in Nature. Human gene transfer is a term used for gene transfer when it is not expected that any therapy will result from the transferred gene, for example, the gene may only be a marker for improving other methods of therapy against the disease. It was first approved in 1989 in the USA. C8.2. Somatic cell gene therapy Somatic-cell gene therapy involves injection of 'healthy genes' into the bloodstream or another target tissue of a patient to cure or treat a hereditary disease or similar illness. The DNA change is not inherited by children. For other types of gene therapy see later in the chapter. The DNA can be repaired by correction of the mutation, which may only require a few base pairs of DNA within a gene to be replaced. Not all the gene must be inserted, only what is needed. If accurate changes can be made it may be very safe. The problem is how to deliver the DNA, and how we can be sure it is changed properly. Many vectors, including modified viruses, have been developed and tested. One success already known is curing an immunodeficiency disease, adenosine deaminase (ADA) deficiency, by allowing expression of the enzyme made from a normal gene in the cells of children lacking it. ADA deficiency is a rare genetic immunodeficiency disease that is caused by lack of functional ADA enzyme. The first human gene therapy protocol began in September 1990 that successfully treated adenosine deaminase deficiency (ADA) disease. If gene therapy is more successful, it will revolutionize the medicine of the future and will have a profound impact on our moral and ethical outlook. But as of 2005 it is still experimental and in clinical trials. Q1. Do you think there are any ethical differences between gene therapy and other therapy? Q2. Does any conventional therapy also change a patient's DNA? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  47. 47. A Cross-Cultural Introduction to Bioethics 144 © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  48. 48. 145 A Cross-Cultural Introduction to Bioethics C8.3. Enzyme Deficiencies and the ADA Gene Therapy trial During the 1980s it was thought that the first patients involved in gene therapy trials would be sufferers of several rare enzyme deficiencies, all with fatal symptoms. Because many genetically determined diseases involve the bone marrow, and bone marrow transplantation techniques are effective for curing many diseases, there have been many preliminary animal gene therapy trials aimed at changing the pluripotent hematopoietic stem cells of the bone marrow, the "parental" cells from which all blood cells come. One of these diseases is ADA deficiency. The lack of the enzyme ADA destroys the immune system. There are up to 5 sufferers of ADA born annually in the USA. The more general name for these diseases is severe combined immunodeficiency (SCID). SCID is extremely rare, affecting about 40 children worldwide each year. About 25 percent of those with SCID suffer from ADA deficiency. ADA degrades certain products that interfere with DNA synthesis, thus killing cells, especially the T-cells of the immune system. The most effective therapy available is complete isolation of the patient so that they are not exposed to infectious agents. Some in the press have called these unfortunate children "bubble" children, because they need to live in a sterile plastic bubble. Bone marrow transplantation can be used if a suitable donor is available. To treat this, the bone marrow is removed from the patient, and then the cells are infected with a virus containing the gene for ADA. The gene then becomes part of the recipient bone marrow cells' DNA along with the carrier virus. After genetic modification in the laboratory the cells are placed back in the patient using bone marrow transplantation and the cells need to continue to produce ADA, they can cure the disease and prevent certain infant death. Up until the late 1980s there was no alternative treatment for sufferers of ADA, a reason why experimental gene therapy methods are used, since they will die if not treated. The major reason that the first trials were postponed in 1990 was that an alternative © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  49. 49. A Cross-Cultural Introduction to Bioethics 146 treatment was partially successful. The new conventional therapy was approved in April 1990, called PEG-ADA, and it combined the protein ADA with another molecule enabling the enzyme to survive intact longer. PEG is a nontoxic polymer. PEG-ADA is not a cure, rather it converts severe combined immunodeficiency to partial combined immunodeficiency. The patients had weekly treatments of PEG-ADA with clinical response to the drug without serious side-effects. Some have been able to go out of isolation and join their families or attend school. In April 1990, Anderson and Blaese and a group of scientists presented their proposal for gene therapy of ADA deficiency to the Human Gene Therapy subcommittee of the U.S. National Institutes of Health. It had many committees (a total of eight layers of review) to pass through before approval, but it was given approval in August 1990 for a trial of ten patients. The test removed T-lymphocytes from the patient and introduced the ADA gene into them. Lymphocytes have a limited life, so the entire procedure needs to be repeated, though they may last many years which is much more than the current life expectancy of these patients. ADA deficiency is a useful model for other diseases that affect the lymphoid system. ADA deficiency is heterogeneous, with patients retaining 0.1 to 5% of the normal level of the enzyme, but this level is still too low for normal immune function. A level of 5% normal is adequate, so the expression of the gene does not need to be great. ADA- deficient T-lymphocytes have normal ADA levels following retrovirally mediated insertion of the normal ADA gene. The presence of the ADA gene inside cells will probably provide better detoxification than the presence of extracellular PEG-ADA. For some children with ADA deficiency, gene therapy has worked as a treatment. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  50. 50. 147 A Cross-Cultural Introduction to Bioethics C8.4. Regulation and Safety; the Gelsinger case Gene therapy is still an experimental therapy, but if it is found to be safe and effective, it may prove to be a better approach to therapy than many current therapies, because gene therapy cures the cause of the disease rather than merely treating the symptoms. Also, many diseases are still incurable by other means, so the potential benefit is saving life. In the USA the trials must be approved by the Recombinant DNA Advisory Committee (RAC) and the FDA. The RAC meetings are open to the public, to help allay fears about genetic engineering. In Japan the trials require approval of committees of both the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health and Welfare. There is extra regulation for gene therapy because it involves genetic engineering, in addition to the normal ethics committee approval for any experimental medicine. From 1989 until September 1999 there were thousands of patients in trials and no one died because of the experiments. 18 year-old Jesse Gelsinger died at the University of Pennsylvania (USA) on 17 September 1999, four days after receiving a relatively high dose of an experimental gene therapy. His death was the result of a large immune reaction to the engineered adenovirus that researchers had infused into his liver. He died of acute respiratory distress syndrome and multiple-organ failure. There was intense review of the procedures for safety following that case. The researchers had not given all the safety data to the patient or regulatory committees. Therefore it was not proper informed consent. (The principles of bioethics and research ethics are discussed in detail in other chapters). The head researcher was also trying to make a company for gene therapy, and may not have reported bad results including deaths of monkeys in the tests because he did not want bad media publicity for the stocks of the company. It was therefore an important case in bioethics in general, and is an example of conflict of interest. The trial at the Pennsylvania Institute for Human Gene Therapy was testing in patients the safety of a possible treatment for an inherited liver disease, ornithine transcarbamylase deficiency (OTCD). OTCD causes ammonia to build up in the blood. Gelsinger’s illness was © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  51. 51. A Cross-Cultural Introduction to Bioethics 148 being partly controlled with a low-protein diet and with a chemical therapy that helps the body eliminate ammonia. The death triggered alarm at many centers that are testing gene therapy, because 30% of all such trials used adenoviruses to convey a gene into patients' cells. Wild adenoviruses can cause various illnesses, including colds, although infections are usually mild. The FDA immediately halted two other trials that involved infusing adenoviruses into patients' livers. The researchers admitted at a meeting of the RAC that they had failed to notify the FDA prior to Gelsinger's fatal reaction of the deaths of some monkeys that had been given high doses of a different modified adenovirus. The group had also omitted to tell the RAC of a change in the way the virus was to be delivered. Also patient volunteers who participated in the OTCD trial before Gelsinger who were mostly given lower doses of virus, still suffered significant liver toxicity. If that had been reported to the FDA, it would likely have put the study on hold. Gelsinger himself should not have been allowed to even join the trial because the approved protocol called for a female in his place, because females are less severely affected by OTCD than males. Furthermore, his blood ammonia level was too high for admission into the trial when it was last checked, on the day before the fatal gene treatment. Following the review of his death, the regulatory systems were made more strict. Then in 2002 there were cases of leukemia in two children in France who had gene therapy for immunodeficiency diseases. However, there was also positive news of gene therapy in some trials for other diseases. Ethically there should be some positive results from animal studies before trials should be approved. The progress since 1989 has not been as fast as many hoped. Non-inheritable (somatic cell) gene therapy to treat patients involves similar ethical issues to any other experimental therapy, and if it is safer and more effective, it should be available. Q3. When was the first trial of gene therapy in your country? What is a clinical trial? © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>
  52. 52. 149 A Cross-Cultural Introduction to Bioethics Q4. How is gene therapy regulated in your country? Q5. Discuss some of the ethical questions raised by the Gelsinger case. C8.5. Germ-line gene therapy At the present the gene therapy that is done is not inheritable. Germ cells are cells connected with reproduction, found in the testis (males) and ovary (females), i.e. egg and sperm cells and the cells that give rise to them. Germ-line gene therapy targets the germ cells that eventually produce gametes (sperm and eggs). This type of therapy may mean injecting DNA to correct, modify or add DNA into the pronucleus of a fertilized egg. The technology requires that fertilization would occur in vitro using the usual IVF procedures (See chapter E2) of super- ovulation and fertilization of a number of egg cells prior to micromanipulation for DNA transfer and then embryo transfer to a mother after checking the embryo's chromosomes. We need to have much wider discussion about the ethical and social impact of human genetic engineering before we start inheritable gene therapy. Deliberately targeting the human germ- line is problematic from biological and ethical viewpoints, especially in view of unknown consequences passed down generations. It may also take away control from the child and person so made. It could lead to consumer children, and there may be no limit in the traits that people can choose. Because of the risk of harm to the development of the person whose genes are changed, many people question its safety as a risk we do not need to take. Other ways could help people who have a child who has a genetic disease, like genetic screening or assisted reproduction and donated gametes. However, others say it is natural for humans to take more control over their evolution. What is happiness? Quality of life. © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508> Being sick is not much fun!
  53. 53. A Cross-Cultural Introduction to Bioethics 150 Q6: What are the ethical differences between inheritable and non-heritable gene therapy? Q7. If you suffered from a disease would you like to correct the genes so that your children do not need to have the same disease or medical therapy that you receive? Q8. If and when gene therapy becomes effective and safe, for what conditions should we allow it? Should it be used to cure a disease, enhance our immune system, or to make our bodies stronger? Q9. Make a list of things that you would not like to change about your body and a list of things you would like to change? In utero gene therapy may be somatic or germ-line. In the 1990s scientists developed a technique in mice in which foreign DNA was transported intravenously to the developing embryo in utero. It was found that the maternal blood flow effectively transported the DNA through the placenta, opening up the way for somatic in utero gene therapy. These advances are significant because they foreshadow the use of in utero gene transfer in humans for specific target organs; such as the lung in the case of cystic fibrosis, targeted for therapy with the advantage of arresting the genetic defect before it can severely damage tissues and organs in affected children. The major hazard of somatic gene therapy, as with all experimental treatments, is that things could go wrong. However, for some diseases irreversible damage is done in utero if the disease is not fixed. The development of human fetal gene therapy, however, carries complex moral and ethical questions including the issues of deliberate or accidental targeting of the germ-line cells with physiological/psychological consequences on future generations of children. Some interesting facts © Eubios Ethics Institute 2005 A Cross-Cultural Introduction to Bioethics < http://www.unescobkk.org/index.php?id=2508>

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