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A Cross-Cultural Introduction to Bioethics

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

switched on or switched off during development and determine our phenotype. Environmental

© Eubios Ethics Institute 2006 Macer, DRJ.,ed. A Cross-Cultural Introduction to Bioethics < http://www.eubios.info/CCIB,htm>

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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?


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C1.2. Mechanism of genetic diseases and mutationsEvery 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.

Figure 1: Mutations alter Amino Acid Sequences


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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)

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


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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

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


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cause cancer.

C1.3. Genetic screeningDNA 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-

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


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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.


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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

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

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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?


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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.


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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?


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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 EngineeringGiven 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


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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.

(See later chapters on human gene therapy and on cloning)

Q9. Please write down your own ethical concerns about genetic engineering.


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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 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


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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

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


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your country? Do they have positive and/or negative effects on your society, economy and environment?


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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 FoodGenetic 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 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

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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 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


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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 FoodSome 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

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


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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?

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.


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C4. Testing for Cancer Gene SusceptibilityChapter 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


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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?

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.

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?


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C4.2. Trash and treasure activity

What to do


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, 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


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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 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.


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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 informationGenes 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. 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

. Collaborating authors: Baoqi Su, China and Darryl Macer, New Zealand


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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?


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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.

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?


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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?


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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.

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


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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?


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C6. The Human Genome ProjectChapter 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

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.


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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?

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;


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http://www.ncbi.nlm.nih.gov/


* 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.


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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.


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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?

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.


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C7. EugenicsFor 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.


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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?


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C8. Human Gene TherapyChapter 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.


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Figure 1: Types of Treatment of Human Genetic DiseaseAfter 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 GenotypePrimary Prevention (e.g. abortion) (Healthy gestation)

Early Death

BirthAbnormal Genotype Normal Genotype

Somatic Cell Gene TherapySecondaryPrevention(e.g. euthanasia)

Disease Symptomatic Therapy HealthAbnormal Genotype Normal Genotype

Germ- line gene therapy

Reproduction(See chapter on fertility)

Sterilization? Donor gametes?

Prenatal diagnosis?

"Healthy" children(see chapter on eugenics)

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What is happiness?Quality of life…

What is happiness?Quality of life.Being sick is not much fun!


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?


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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 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.


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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.


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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


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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?


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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.


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What is happiness?Quality of life.Being sick is not much fun!


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

The first approved gene transfer was in 1989 in USA, and it involved the use of cells which

attack cancer, called tumour-infiltrating lymphocytes (TILs). They are isolated from the

patient's own tumour, then grown in large number in vitro. The cells are then returned to the

patient and stimulated by a naturally-occuring hormone, interleukin-2. The procedure was


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found to help about a half of the patients. In order to discover how this therapy works, the

TILs were genetically marked to trace them in the patients. The initial trial involved ten

patients, but later that number was increased following the success of the preliminary group of

patients.

The first country to issue a commercial license to somatic cell gene therapy was China, for a

cancer treatment! There are trials in many countries, and despite discussions since the 1960s of

the ethics of the techniques, it has not yet proven to be of widespread applicability. As we

improve our understanding of genetics, immunology and our body, it is hoped that it will

deliver on its promise. It goes to show how long it can take to conduct medical research to

provide a clinically effective treatment.


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C9. Universal Declaration on the Human

Genome and Human Rights UNESCO Unanimously approved this statement on 11 November, 1997 at the General Conference, after numerous drafts from the International Bioethics Committee (from 1993-1997). The United Nations General Assembly unanimously endorsed it on 9 December, 1998. Please consider the first global bioethics declaration. Do you agree?

The General Conference [of member countries of UNESCO],

Recalling that the Preamble of UNESCO's Constitution refers to "the democratic principles of

the dignity, equality and mutual respect of men", rejects any "doctrine of the inequality of men

and races", stipulates "that the wide diffusion of culture, and the education of humanity for

justice and liberty and peace are indispensable to the dignity of men and constitute a sacred

duty which all the nations must fulfil in a spirit of mutual assistance and concern", proclaims

that "peace must be founded upon the intellectual and moral solidarity of mankind", and states

that the Organization seeks to advance "through the educational and scientific and cultural

relations of the peoples of the world, the objectives of international peace and of the common

welfare of mankind for which the United Nations Organization was established and which its

Charter proclaims",

Solemnly recalling its attachment to the universal principles of human rights, affirmed in

particular in the Universal Declaration of Human Rights of 10 December 1948 and in the two

International United Nations Covenants on Economic, Social and Cultural Rights and on Civil

and Political Rights of 16 December 1966, in the United Nations Convention on the

Prevention and Punishment of the Crime of Genocide of 9 December 1948, the International

United Nations Convention on the Elimination of All Forms of Racial Discrimination of 21

December 1965, the United Nations Declaration on the Rights of Mentally Retarded Persons

of 20 December 1971, the United Nations Declaration on the Rights of Disabled Persons of 9

December 1975, the United Nations Convention on the Elimination of All Forms of


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Discrimination Against Women of 18 December 1979, the United Nations Declaration of

Basic Principles of Justice for Victims of Crime and Abuse of Power of 29 November 1985,

the United Nations Convention on the Rights of the Child of 20 November 1989, the United

Nations Standard Rules on the Equalization of Opportunities for Persons with Disabilities of

20 December 1993, the Convention on the Prohibition of the Development, Production and

Stockpiling of Bacteriological (Biological) and Toxin Weapons and on their Destruction of 16

December 1971, the UNESCO Convention against Discrimination in Education of 14

December 1960, the UNESCO Declaration of the Principles of International Cultural Co-

operation of 4 November 1966, the UNESCO Recommendation on the Status of Scientific

Researchers of 20 November 1974, the UNESCO Declaration on Race and Racial Prejudice of

27 November 1978, the ILO Convention (N° 111) concerning Discrimination in Respect of

Employment and Occupation of 25 June 1958 and the ILO Convention (N° 169) concerning

Indigenous and Tribal Peoples in Independent Countries of 27 June 1989,

Bearing in mind, and without prejudice to, the international instruments which could have a

bearing on the applications of genetics in the field of intellectual property, inter alia the Bern

Convention for the Protection of Literary and Artistic Works of 9 September 1886 and the

UNESCO Universal Copyright Convention of 6 September 1952, as last revised in Paris on 24

July 1971, the Paris Convention for the Protection of Industrial Property of 20 March 1883, as

last revised at Stockholm on 14 July 1967, the Budapest Treaty of the WIPO on International

Recognition of the Deposit of Micro-organisms for the Purposes of Patent Procedures of 28

April 1977, and the Trade Related Aspects of Intellectual Property Rights Agreement (TRIPs)

annexed to the Agreement establishing the World Trade Organization, which entered into

force on 1st January 1995,

Bearing in mind also the United Nations Convention on Biological Diversity of 5 June 1992

and emphasizing in that connection that the recognition of the genetic diversity of humanity

must not give rise to any interpretation of a social or political nature which could call into

question "the inherent dignity and (...) the equal and inalienable rights of all members of the

human family", in accordance with the Preamble to the Universal Declaration of Human

Rights,


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Recalling 22 C/Resolution 13.1, 23 C/Resolution 13.1, 24 C/Resolution 13.1,

25 C/Resolutions 5.2 and 7.3, 27 C/Resolution 5.15 and 28 C/Resolutions 0.12, 2.1 and 2.2,

urging UNESCO to promote and develop ethical studies, and the actions arising out of them,

on the consequences of scientific and technological progress in the fields of biology and

genetics, within the framework of respect for human rights and fundamental freedoms,

Recognizing that research on the human genome and the resulting applications open up vast

prospects for progress in improving the health of individuals and of humankind as a whole, but

emphasizing that such research should fully respect human dignity, freedom and human rights,

as well as the prohibition of all forms of discrimination based on genetic characteristics,

Proclaims the principles that follow and adopts the present Declaration.

A. HUMAN DIGNITY AND THE HUMAN GENOME

1. The human genome underlies the fundamental unity of all members of the human family, as

well as the recognition of their inherent dignity and diversity. In a symbolic sense, it is the

heritage of humanity.

2. a) Everyone has a right to respect for their dignity and for their rights regardless of their

genetic characteristics.

b) That dignity makes it imperative not to reduce individuals to their genetic characteristics

and to respect their uniqueness and diversity.

3. The human genome, which by its nature evolves, is subject to mutations. It contains

potentialities that are expressed differently according to each individual's natural and social

environment including the individual's state of health, living conditions, nutrition and

education.

4. The human genome in its natural state shall not give rise to financial gains.

B. RIGHTS OF THE PERSONS CONCERNED

5. a) Research, treatment or diagnosis affecting an individual's genome shall be undertaken

only after rigorous and prior assessment of the potential risks and benefits pertaining thereto


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and in accordance with any other requirement of national law.

b) In all cases, the prior, free and informed consent of the person concerned shall be obtained.

If the latter is not in a position to consent, consent or authorization shall be obtained in the

manner prescribed by law, guided by the person's best interest.

c) The right of each individual to decide whether or not to be informed of the results of genetic

examination and the resulting consequences should be respected.

d) In the case of research, protocols shall, in addition, be submitted for prior review in

accordance with relevant national and international research standards or guidelines.

e) If according to the law a person does not have the capacity to consent, research affecting his

or her genome may only be carried out for his or her direct health benefit, subject to the

authorization and the protective conditions prescribed by law. Research which does not have

an expected direct health benefit may only be undertaken by way of exception, with the utmost

restraint, exposing the person only to a minimal risk and minimal burden and if the research is

intended to contribute to the health benefit of other persons in the same age category or with

the same genetic condition, subject to the conditions prescribed by law, and provided such

research is compatible with the protection of the individual's human rights.

6. No one shall be subjected to discrimination based on genetic characteristics that is intended

to infringe or has the effect of infringing human rights, fundamental freedoms and human

dignity.

7. Genetic data associated with an identifiable person and stored or processed for the purposes

of research or any other purpose must be held confidential in the conditions set by law.

8. Every individual shall have the right, according to international and national law, to just

reparation for any damage sustained as a direct and determining result of an intervention

affecting his or her genome.

9. In order to protect human rights and fundamental freedoms, limitations to the principles of

consent and confidentiality may only be prescribed by law, for compelling reasons within the

bounds of public international law and the international law of human rights.

C. RESEARCH ON THE HUMAN GENOME


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10. No research or research applications concerning the human genome, in particular in the

fields of biology, genetics and medicine, should prevail over respect for the human rights,

fundamental freedoms and human dignity of individuals or, where applicable, of groups of

people.

11. Practices which are contrary to human dignity, such as reproductive cloning of human

beings, shall not be permitted. States and competent international organizations are invited to

co-operate in identifying such practices and in taking, at national or international level, the

measures necessary to ensure that the principles set out in this Declaration are respected.

12.a) Benefits from advances in biology, genetics and medicine, concerning the human

genome, shall be made available to all, with due regard for the dignity and human rights of

each individual.

b) Freedom of research, which is necessary for the progress of knowledge, is part of freedom

of thought. The applications of research, including applications in biology, genetics and

medicine, concerning the human genome, shall seek to offer relief from suffering and improve

the health of individuals and humankind as a whole.

D. CONDITIONS FOR THE EXERCISE OF SCIENTIFIC ACTIVITY

13. The responsibilities inherent in the activities of researchers, including meticulousness,

caution, intellectual honesty and integrity in carrying out their research as well as in the

presentation and utilization of their findings, should be the subject of particular attention in the

framework of research on the human genome, because of its ethical and social implications.

Public and private science policy-makers also have particular responsibilities in this respect.

14. States should take appropriate measures to foster the intellectual and material conditions

favourable to freedom in the conduct of research on the human genome and to consider the

ethical, legal, social and economic implications of such research, on the basis of the principles

set out in this Declaration.

15. States should take appropriate steps to provide the framework for the free exercise of

research on the human genome with due regard for the principles set out in this Declaration, in

order to safeguard respect for human rights, fundamental freedoms and human dignity and to


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protect public health. They should seek to ensure that research results are not used for non-

peaceful purposes.

16. States should recognize the value of promoting, at various levels as appropriate, the

establishment of independent, multidisciplinary and pluralist ethics committees to assess the

ethical, legal and social issues raised by research on the human genome and its applications.

E. SOLIDARITY AND INTERNATIONAL CO-OPERATION

17. States should respect and promote the practice of solidarity towards individuals, families

and population groups who are particularly vulnerable to or affected by disease or disability of

a genetic character. They should foster, inter alia, research on the identification, prevention

and treatment of genetically-based and genetically-influenced diseases, in particular rare as

well as endemic diseases which affect large numbers of the world's population.

18. States should make every effort, with due and appropriate regard for the principles set out

in this Declaration, to continue fostering the international dissemination of scientific

knowledge concerning the human genome, human diversity and genetic research and, in that

regard, to foster scientific and cultural co-operation, particularly between industrialized and

developing countries.

19. a) In the framework of international co-operation with developing countries, States should

seek to encourage measures enabling:

1. assessment of the risks and benefits pertaining to research on the human genome to be

carried out and abuse to be prevented;

2. the capacity of developing countries to carry out research on human biology and genetics,

taking into consideration their specific problems, to be developed and strengthened;

3. developing countries to benefit from the achievements of scientific and technological

research so that their use in favour of economic and social progress can be to the benefit of all;

4. the free exchange of scientific knowledge and information in the areas of biology, genetics

and medicine to be promoted.

b) Relevant international organizations should support and promote the initiatives taken by

States for the abovementioned purposes.


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F. PROMOTION OF THE PRINCIPLES SET OUT IN THE DECLARATION

20. States should take appropriate measures to promote the principles set out in the

Declaration, through education and relevant means, inter alia through the conduct of research

and training in interdisciplinary fields and through the promotion of education in bioethics, at

all levels, in particular for those responsible for science policies.

21. States should take appropriate measures to encourage other forms of research, training and

information dissemination conducive to raising the awareness of society and all of its

members of their responsibilities regarding the fundamental issues relating to the defense of

human dignity which may be raised by research in biology, in genetics and in medicine, and

its applications. They should also undertake to facilitate on this subject an open international

discussion, ensuring the free expression of various socio-cultural, religious and philosophical

opinions.

G. IMPLEMENTATION OF THE DECLARATION

22. States should make every effort to promote the principles set out in this Declaration and

should, by means of all appropriate measures, promote their implementation.

23. States should take appropriate measures to promote, through education, training and

information dissemination, respect for the abovementioned principles and to foster their

recognition and effective application. States should also encourage exchanges and networks

among independent ethics committees, as they are established, to foster full collaboration.

24. The International Bioethics Committee of UNESCO should contribute to the dissemination

of the principles set out in this Declaration and to the further examination of issues raised by

their applications and by the evolution of the technologies in question. It should organize

appropriate consultations with parties concerned, such as vulnerable groups. It should make

recommendations, in accordance with UNESCO's statutory procedures, addressed to the

General Conference and give advice concerning the follow-up of this Declaration, in particular

regarding the identification of practices that could be contrary to human dignity, such as germ-

line interventions.

25. Nothing in this Declaration may be interpreted as implying for any State, group or person


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any claim to engage in any activity or to perform any act contrary to human rights and

fundamental freedoms, including the principles set out in this Declaration.


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