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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
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 mutations
Every person has a different genetic sequence except for identical twins. The genes
are made of DNA. DNA is a long chain of units, called bases, and there are only four kinds of
base (ATCG). Each position of the DNA can be one of the four bases, and the genetic
sequence is the order of these bases. In the same way the sequence of this sentence determines
what we understand in reading it, the sequence of DNA determines what happens in living
organisms. There are only four possible characters for each position, but even a short sequence
of 20 positions could have many possible combinations of sequence. DNA is a long chain of
these units, which forms a spiral geometrical structure called a double helix.
Functional lengths of DNA are called genes. Each gene may be involved in defining
one particular function or character at the phenotypic level. There are many new genes
discovered every week. Our genes are in long linear strings, called chromosomes. Humans
possess 23 different pairs of chromosomes, a total of 46. While every human has the same set
of chromosomes and thus types of genes in the same order, each gene has variant types which
are called alleles. Alleles differ in their exact sequence of DNA but they should generally
perform the same function. We can have many different alleles, for example there are at least
46 distinct alleles of the gene phenylalanine hydroxylase (e.g., a mutated allele of this gene is
responsible for the disease PKU). There are mutations found in each of these alleles, which
would make total genetic screening for PKU impracticable, but a simple cheap enzyme test
can be performed.
Mutations are changes in the nucleotide base sequence, and are quite common.
Mutations can be caused by random chance, by chemicals or radiation, and most commonly
are caused by reactive chemicals (free radicals) formed in the ordinary process of metabolism.
Specific mutations are often seen as a response to ultraviolet (UV) light or smoking. The DNA
repair enzymes can repair most of these, others may escape repair and can result in
abnormalities, such as cancer. If the mutation occurs in the zygote, or reproductive (germ)
cells, the new offspring may carry the mutation. Somatic mutations play a role in the
development of most cancers, being steps in the process. Only some mutations actually cause
harm, others may make no harm (see Fig. 1). This complex system is in delicate balance, and
it only requires a defect in a single gene to disrupt this balance, the effect sometimes being
lethal.
Figure 1: Mutations alter Amino Acid Sequences
The original and the mutated DNA sequences may give rise to the same amino acid, a different
amino acid, or stop translation. A frameshift mutation completely alters the amino acid
sequence resulting in a nonsense message.
DNA Sequence
Protein Sequence
Original
AACTAATTGCGTA
Leu-Ile-Asp-AlaNeutral Mutation
AACTAGTTGCGTA
Leu-Ile-Asp-AlaSingle amino acid change
AACTACTTGCGTA
Leu-Met-Asp-AlaDeletion, frameshift
AACT/ATTGCGTA
Leu-Ile-Thr-HisInsertion, 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
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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
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
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sperm) and others in the body (somatic) cells. Both types of mutation have the potential to
cause cancer.
C1.3. Genetic screening
DNA is normally found in double-stranded form (the double helix). The four bases
are given the symbols, A, T, G, and C. The base A binds with T, and the base G binds with C,
between these long chains, as is shown below:
---ATTCCGAAGCTGACTGA--- parent chain
---TAAGGCTTCGACTGACT--- complementary
Genetic screening involves the use of this complementary binding. A sample of DNA
is taken from a cell, and then the DNA is split into single chains. The bases in this
single-stranded DNA will bind to the pairing bases. To make it easier to test, this
single-stranded DNA may be fixed to a plastic filter. We can test for the presence of a certain
sequence in this fixed DNA by adding a solution of single-stranded probe DNA, a short
sequence of synthetically made DNA with a label on it, like a fluorescent dye. After mixing
the probe with the sample, the probe that is not bound to the complementary sequence is
washed away. If there are copies of the sequence in the sample, we will be able to see the
probe when we hold the filter under ultraviolet light, because the probe is fluorescent. If there
is no complementary sequence in the sample to the probe, then we will not see any
fluorescence.
In this way, many samples can be tested, with many probes, and this is known as
genetic screening. We screen for the presence or absence of particular DNA sequences that
represent different genes. This screening can be used to detect a mutation, for example to tell
that a fetus has a mutation that will cause a genetic disease (prenatal diagnosis). It can also be
used to detect which types of bacteria may be present in a food sample, or for medical
diagnosis of a patient.
Information about whether an individual has a particular DNA sequence and gene can
be very powerful, especially in the diagnosis of genetic disease. There are many ethical and
legal issues that result from this technology, as discussed in following chapters on genetic
privacy and information. For example, presymptomatic screening means testing for a
late-onset genetic disease, like Huntington's disease, before the person is sick. Such predictive
power may require psychological counseling. It is very important that privacy is respected,
because the information in a person's genes identifies risk factors for disease that medical
insurance companies and employers could use to discriminate against people. There are
already cases of discrimination against individuals after genetic testing in North America.
Many genetic diseases (such as diabetes or cancer) are caused by the effects of
multiple genes, and the relationship between the environment and genes. Genetic
susceptibility means that a particular gene is only one determinant for the development of a
complex disorder. For example to have an allele called Apo E4 (that about 10% of Caucasians
and Asians have) increases the risk of developing Alzheimer's disease, and confers a very
strong susceptibility at younger age if you have two alleles. Alternatively, another allele for
this gene, Apo E2, seems to be protective against Alzheimer's.
Q4. Is there any advantage to having presymptomatic screening for
Alzheimer's disease when you are 20 years old? What about when you are 60
years old?
Q5. If you check on the Internet for keywords like “gene array” or “gene test”,
you can find many examples of genetic tests. Find some examples and write
about the advantages and disadvantages of genetic screening.
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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
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.
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 Engineering
Given that the technology is new, has immense potential, is rapidly developing, and
can be applied to all living beings, it can be used for beneficial purposes but there are also
risks. It is a sophisticated technology and needs developed laboratory facilities and particular
environmental conditions that require investment. Many kinds of GMOs are developed for
environmental purposes and for health and medicine. Genetic engineering has been
particularly successfully used and applied in food and agriculture to produce genetically
modified foods (See a separate chapter C3).
Because genetic engineering is still considered a new technology, some doubts, fears,
concerns have been raised. Let us consider extrinsic ethical concerns and intrinsic ethical
concerns.
a) Extrinsic concerns are based on doubts about the technology, its potentiality, newness and
applicability to all life forms. There are fears of human misuse of technology, for example for
biowarfare or eugenics. There are fears of environmental damage to other organisms or
ecosystems. The people in favour of technology think that genetic modification provides a
great opportunity for feeding people or treating sick persons with new medical products. The
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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.
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.
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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
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
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 Food
Genetic engineering or genetic modification alters the genetic constitution of organisms
by mixing the DNA of different genes and species together. The living organisms made with
altered DNA are called Genetically Modified Organisms (GMOs). Genetic engineering is
considered special because often the techniques involves manipulating genes in a way that is
not expected to occur ordinarily in nature, that characters can be changed between species.
Many kinds of GMOs have been developed for environmental purposes and for health
and medicine. Genetic engineering has been particularly successfully used and applied in food
and agriculture to produce genetically modified (GM) foods.
Use of genetic engineering technologies in food and agriculture to produce GM food has
been very controversial. Genetic engineering has been used to produce transgenic plants that
carry several enhanced characteristics by inserting genes from various organisms, for example,
plants with increased yield, disease resistance, and pest resistance with inserted Bacillus
thuriengensis (Bt) insecticidal protein genes which selectively kill pests that eat crops. There
have also been fruits and vegetables modified for long term storage or delayed ripening that
remain fresh for a long time, which is also useful during transportation to the market. Over
15 countries of the world used GM crops for general food production by 2004.
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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
quickly? What other agricultural uses of genetic engineering do you
know?
Q4. Do you think golden rice is a "good" GM food? What other information
do you need to make a judgment?
C3.3. Ethical issues of GM Food
Some people think that products made from GMOs are unnatural. Some call them as
Franken-foods. We need to think about whether they are different from existing food varieties.
It is not possible for the consumer to differentiate GM food from other conventionally grown
foods since both look the same, may even taste the same, unless it is mentioned on the labels
of the packets. It is difficult to say that the food is unsafe given that in some parts of the
world, like in the USA, people have been eating GM food for a decade. In other parts of the
world, especially in Europe, many people are not willing to accept GM food because of fears
of health risks and other ethical concerns.
We can find people with allergies to many foods, and there will always be some
people who have an allergy. That is another reason why people may need to know what is in
the food. In the modern supermarket however, most foods are processed containing some
compounds from many different plants, especially soybeans.
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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
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 Susceptibility
Chapter objectives.
Breast cancer kills more women than it does men, but it is
a question that faces all in society.
This chapter aims to consider:
1. genetic testing using the example of breast cancer.
2. risks and benefits of genetic testing.
3. limitations of genetic testing.
C4.1. Testing for cancer gene susceptibility
Genetic testing is based on knowing the genetic code of
cells in our bodies. This genetic code, in the
form of the chemical DNA, determines everything
from hair colour to the way we digest food.
Mutations, or changes to the structure of DNA, can
make us more susceptible to some diseases or disabilities.
Even if you have a mutation, it may not mean you will get
the disease, but just that you are more likely to get it. The
link between having the mutation and the possibility of
getting the disease is not well understood. For example,
some genetic mutations interact with factors like a person’s
lifestyle or other environmental factors such as chemicals or sunlight.
The technology for testing for some mutations is now available. Imagine that a simple blood
test could tell you if you have a mutated gene that makes you susceptible to getting cancer.
There may be the possibility that you could pass this mutation on to your unborn children.
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?
Collaborating author: Lindsey Conner, New Zealand
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Q1. If your sister tests positive for the BRCA1 gene, would you recommend to
her that she have her breasts or ovaries removed as a preventative measure?

C4.2. Trash and treasure activity
A researcher must dig to find words to help answer the questions (treasure) and
toss aside unnecessary sentences, phrases, words, ideas as trash because they do
not answer the questions and therefore are unimportant in this context.
What to do
Choose ONE question from the list below and write it on a piece of paper.
A.
What are the advantages of being screened for the breast cancer gene BRCA1?
B.
Why do women who are tested need counselling?
C.
What are the implications for a person who is tested to be positive for the gene?
D.
What are the implications if the test is negative?
1.
Scan the text (C4.3) sentence by sentence to find the answer. Ask “Does this sentence
answer the question (A, B, C and D)?”
2.
If it does not answer the question, it is trash. Go on to the next sentence.
3.
If it does answer the question treasure it by writing down the words or phrase that
answers the question.
4.
Continue to read the text until you have finished sorting the trash and treasure. Make
sure you keep all the treasure as notes.
C4.3. BRCA testing
Changes to the gene BRCA1 have been linked with breast and ovarian cancer. BRCA1 is a
tumour suppressor gene. Tumour suppressors are genes that control cell growth. When enough
cells in an area have grown, the tumour suppressors tell the cells to stop growing. When these
genes don’t work properly, as in the case of mutated BRCA1 genes, 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.
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Genetic testing can lead to early detection that could help to prolong and save lives. The
information could cause havoc if it was misused or misunderstood. When a woman is told that
she carries the gene, she has the following options. She could simply monitor her health. In the
case of ovarian cancer this may not be enough as often symptoms do not appear until it is too
late. She could choose to have a preventative mastectomy (surgery to remove her breasts) or
hysterectomy (surgery to remove either just the ovaries or the uterus and the ovaries).
Making the decision and having an operation can cause stress. People deal with stress in
different ways. Some people become devastated. This may lead to anxiety attacks, depression
or even heart disease.
Some people, even if they cannot change their future, find information of this sort
beneficial.... the more they know, the more their anxiety level goes down. But there are others
who cope by avoiding, who would rather stay hopeful and optimistic and not have difficult
questions answered. Some people feel they would have more control over their health if they
knew they had inherited a defective gene. Some women might choose to have their children
early in life and then proceed with a hysterectomy. And others feel they simply could not
adjust to a positive test result.
This type of testing can have enormous implications on future employment or health and
life insurance eligibility. Suppose a person learns that they have a predisposition to cancer;
would they be forced to inform their employers and insurers about the test results? Potential
employers may hold this information against them and not offer them the job. If insurance
companies were given this information, premiums would increase for those at risk and life
insurance may be denied.
There are also implications should a person test negative, as this result may lead to people
feeling that will not get cancer (complacency). A woman might decide not to monitor her
health carefully, neglecting the early detection practices such as self- exam 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 information
Genes largely determine who we take after in our family, and usually we can see a mixture of
our father and mother, and someone new. Human cells have 46 chromosomes, 23 from each
parent. Each chromosome is composed of a very large single deoxyribonucleic acid (DNA)
molecule. A DNA molecule consists of two strands that wrap around each other in a twisted
ladder conformation called a “double helix”. Each ladder rung consists of a pair of chemicals
called bases, either A (adenine) and T (thymine) or C (cytosine) and G (guanine). There are
over three billion of these base pairs of DNA making up the human genome. Genes are made
of DNA. They code the directions for building all of the proteins that make our body
function. Except for identical twins, every person has a different genetic sequence. Variation
of this sequence, and the responses to environmental factors, accounts for human diversity.
There are different types of genetic information. The genotype of a person is all the DNA they
have. It provides details, at the fundamental level of DNA or protein sequence. Phenotype is
the observable outcome in terms of physical characteristics. In many cases the phenotype is a
result of the interaction between genotype and environmental factors, for example, our body
weight. Information about a person’s physical features and gene-inherited diseases are part of
the individual’s genetic information.
Q1. What genetic factors determine whether
we are man or woman?
Q2. Think about what characters are determined
by genetics and which are determined by the
environment.
Q3
.
Would you like to know your genes?
Collaborating authors: Baoqi Su, China and Darryl Macer, New Zealand
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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
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 Project
Chapter objectives
The Human Genome Project has been the project to
sequence all human DNA and map the genes and DNA
sequences that determine genetic variation. There have
also been many other species as subjects of their own
genome projects, which provides interesting biological
information fundamental for understanding how to apply
biotechnology to practical use. This chapter aims to
introduce:
1. The human genome project.
2. The roles of the International Human Genome
Organization.
3. Some examples of other genomes being sequenced.
C6.1. The Human Genome Project
The Human Genome Project (HGP) aimed to map and sequence all the DNA of human
beings, known as the genome (a total of about 2.8 billion linear bases on 23 different
chromosomes). There are thought to be about 30,000 genes in human beings, and most of
these have been identified. However, the genes comprise only 5-10% of the total DNA in the
human genome, the function of the rest of the DNA is unknown. While most genes have been
identified, the function of most of them is still to be investigated.
The Human Genome Project was conducted by a publicly financed international
research effort whose goal was to decipher the human genetic code and to provide these data
freely and rapidly to the public. In addition a company called Celera, and several others, also
made intensive efforts to sequence the human genome. On June 26, 2000, members of the
Human Genome Project announced that they had succeeded in sequencing a "working draft"
of the human genome. An article published in the February 15, 2001 issue of the journal
Nature outlines the strategies and methodologies used by this group to generate the draft
sequence.
Sequencing of the human genome represents a scientific milestone, and the data are of
immediate use in many important ways. To further understand and use the information coded
for in this "human blueprint", several international bodies, including the U.S. National Center
for Biotechnology Information (NCBI) provide access to these data worldwide through public
Web sites (http://www.ncbi.nlm.nih.gov).
The Human Genome Organisation (HUGO) was conceived in late April 1988, at the
first meeting on genome mapping and sequencing at Cold Spring Harbor, New York state,
USA. For some time, as the genome initiatives got under way in individual nations, the need
for an international coordinating scientific body had been under discussion.
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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;
* 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. Eugenics
For millennia there have been attempts to improve hereditary qualities through selective
breeding. Eugenics can be defined "as any effort to interfere with individuals' procreative
choices in order to attain a societal goal". The word means "good breeding" from the Greek
names Eugene and Eugenia expressing the notion of "well born" which was a celebration of
parents’ belief that their offspring are especially blessed.
The term "eugenics" was coined by Sir Francis Galton, an English scientist (1822-1911),
based on studies of hereditary and Mendelian genetics. The eugenic idea has been abused in
the past; for example, by the Nazis in the 1930s and early 1940s. Some countries have
implemented social policies to promote eugenic population selection even today, including
immigration policies and reproductive technology, but generally modern eugenics is based on
eliminating genetic disorders. Several forms include:
Eugenics of normalcy: Policies and programs intended to ensure that each individual has at
least a minimum number of normal genes.
Negative eugenics: Policies and programs intended to reduce the occurrence of genetically
determined disease. Many countries sterilized persons to stop them having children in the
twentieth century.
Positive eugenics: The achievement of systematic or planned genetic changes to improve
individuals or their offspring. This includes selection of healthy genes, and use of gametes
from people thought to be superior in intelligence or physical characters.
When abused it has been developed into genocide and "ethnic cleansing". Ethnic cleansing is
the mass expulsion or extermination of people from a minority ethnic or religious group within
a certain area and who, in many instances, had lived in harmony for generations prior to the
outbreak of national hostilities. Well publicized examples include ethnic atrocities experienced
in the former Yugoslavia. War violates fundamental human decency but is at its worst when
actions are taken against civilian populations subjected to atrocities such as rape,
assassinations, massacres, torture and ethnic cleansing.
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 Therapy
Chapter objectives
Gene therapy has been discussed since the 1970s but
despite clinical trials since 1990 it has not yet been very
successful. It is however a symbolic issue in bioethics, for
it is a technology that was discussed prior to its use widely
in many societies from the ethical perspective.
This chapter aims to:
1. Introduce somatic cell and germ-line gene therapy.
2. Consider the risks and benefits of gene therapy.
3. Investigate the relationship between discussion of
ethics and evolution of regulation.
4. Consider human genetic engineering.
C8.1. Gene Therapy trials
Many genetic diseases may be able to be treated by correcting the defective genes, using gene
therapy. Gene therapy is a therapeutic technique in which a functioning gene is inserted into
the somatic (body) cells of a patient to correct an inborn genetic error or to provide a new
function to the cell. It means the genetic modification of DNA in body cells of an individual
patient, directed to alleviating disease in that patient. There have been several hundred human
gene therapy clinical trials in many countries (including USA, EU, Canada, China, Japan, New
Zealand…), involving over 6000 patients world-wide, for several different diseases including
several cancers.
Genetic engineering is altering the genetic composition of a living organism by technological
means based on recombinant DNA technology (see Chapter C2). This can involve altering
the gene sequence, or addition, substitution, and/or deletion of DNA. It has contributed to the
understanding of genetic diversity which is useful in the conservation of plants, animals and
microorganisms. Genetic intervention is a general term for the modification of inheritable
characteristics of individuals or populations through various social mechanisms and/or
biomedical technologies.
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Figure 1: Types of Treatment of Human Genetic Disease
After conception the genotype may be "normal" (without a genetic disease) or "abnormal" (with
a genetic disease). There are several stages at which therapy could occur. Somatic cell therapy
can be performed before birth or after. Symptomatic therapy (to treat the symptoms of the
disease by diet or medicine for example) usually occurs after birth, but may also occur before
birth in some diseases where it is possible and necessary to treat early. The questions of
reproduction are more complex, as someone healthy in their life may still have problems with
their fertility or pass on a genetic disease to their children.
Conception
Gene Therapy on
Embryo or Fetus
Abnormal Genotype
Primary
Prevention (e.g. abortion)
Normal Genotype
(Healthy gestation)
Early Death
Birth
Abnormal Genotype
Somatic Cell
Secondary
Prevention
(e.g. euthanasia)
Disease
Symptomatic
Normal Genotype
Gene Therapy
Health
Therapy
Abnormal Genotype
Normal Genotype
Germ- line
gene therapy
Reproduction
What is
happiness?
Quality of
(See chapter on fertility)
Sterilization?
Donor gametes?
Prenatal diagnosis?
"Healthy" children
(see chapter on eugenics)
life…
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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.
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
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.
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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?
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
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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.
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
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
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,
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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,
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.
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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
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
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.
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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
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;
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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.
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
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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