Genes and human health - the science and ethics
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1 Deoxyribonucleic acid (DNA) - why is it so important? Genes and human health - the science and ethics DNA is essential to all living organisms, from bacteria to man, as it contains a code which specifies the synthesis of proteins that are required for living cells to function. DNA is a polymer of four essential building blocks known as nucleotides. Each nucleotide contains three chemical components, a sugar (deoxyribose), phosphoric acid, and one of four nitrogenous bases (abbreviated to A, C, G and T, see Figure 1). The nucleotides are joined together by chemical bonds between deoxyribose and phosphoric acid to make long polynucleotide chains. These chains (or strands ) can extend to 100s of millions of nucleotides in length. DNA molecules are actually made up of two separate polynucleotide chains held together by hydrogen bonds between the nitrogenous bases i.e. they are double-stranded. The two strands are antiparallel, the nucleotides in one chain point in the opposite chemical direction to nucleotides in the other chain (see Figure). Now this is where things start to get really interesting with DNA! The rules concerning base pairing in opposing strands are very simple, but strict, and this explains several functional properties of DNA. Quite simply a T in one strand is always paired with an A in the opposite strand, and G in one strand is always paired with a C in the opposite strand. This A with T and C with G rule is known as complementary base-pairing and has important implications for the way DNA is replicated, and how information in DNA is translated into specific protein sequences. A good way to think about the structure of DNA is as follows- think of the overall structure as a ladder where the two different strands make the two uprights, and the complementary base pairs form the rungs. The ladder is then twisted to generate the characteristic helical shape of DNA (see Figure 1). Web Figure 10.1 DNA. Used with permission under the terms of the GNU Free Documentation License.
2 The complementary base-pairing rule explains one very important property of DNA, i.e. how it is accurately replicated when cells divide. In the cells of our bodies, like most other animals, plants, and fungi, DNA is located in the nucleus and is organised into structures called chromosomes. Each chromosome contains a long double-stranded DNA molecule. Before cells divide the DNA in each chromosome has to be replicated and then partitioned into two daughter cells. This process is repeated for each chromosome in a cell and ensures that each daughter cell contains ALL of the original genetic information present in the parental cell. Accurate replication of DNA is governed by the complementary base-pairing rule. When a DNA molecule replicates the two component strands are separated and enzymes known as DNA polymerases use the four nucleotide building blocks to construct two new double-stranded DNA molecules using each of the parental strands as a template. You can imagine the DNA polymerase scanning a single-stranded template and when it encounters a T on the template strand it will incorporate an A opposite it. If it next encounters a C on the template it will incorporate a G. As it reads along the template it polymerises the new nucleotides into a new strand which is complementary to the template strand. This process is repeated on both parental templates and the result is two copies of the original DNA! When James Watson and Francis Crick first unravelled the structure of DNA in 1953 they immediately realised that the structure of DNA readily explained how it could replicate. Information content in DNA An obvious question that arose from our knowledge of the structure of DNA was how a polymer built from just four different building blocks could encode the information that specifies the development and function of organisms as complex as humans. Information encoded in DNA is required to direct the synthesis of proteins. Like DNA, proteins are also polymers but they are made from different building blocks called amino acids, of which there are 20. The specific order of amino acids in a protein determines its biological activity and this information is specified by the order of nucleotide bases in DNA. DNA molecules are very long and in some chromosomes the molecules are made up of 100s of millions of base pairs. Specific regions of these DNA molecules correspond to genes and the order of the four nucleotide bases in genes specifies the order of amino acids in a particular protein. The actual mechanism of information transfer is quite complex. Firstly, one DNA strand of a gene acts as a template for the synthesis of a closely related single-stranded nucleic acid molecule called messenger RNA (mrna- see Figure). mrna has similar bases to DNA (except for one) and its synthesis is controlled using the same base-pairing rules as in DNA synthesis. This process is termed transcription. In protein synthesis each successive block of three bases in mrna is termed a codon and this specifies a particular amino acid, the next codon in the mrna chain specifies the next amino acid and the adjacent amino acids are joined together as successive codons in the mrna are deciphered. This process is collectively known as translation and explains how the sequence of nucleotide bases in a DNA molecule can specify the sequence of amino acids in a protein (see Figure 2).
3 Figure 2 DNA translation So, what about our DNA? Humans are diploid organisms. This means that each of the cells in our bodies contains two copies of each chromosome, and there are 23 pairs (46 chromosomes) in total (see Figure below). We all started life as a single celled zygote, the result of a fertilisation event between an egg cell from our mother and a sperm cell from our father. The egg and sperm each contained a single copy of each of the 23 chromosomes and the fertilisation event generated a cell with a diploid set of chromosomes. The Human Genome Project aimed to decode the complete sequence of bases in the DNA of each chromosome so that the number and nature of genes required for human life could be determined. The results of this project were very surprising! Firstly, we have a massive amount of DNA in each of the diploid cells of our body, about 6 billion base pairs in total! If you joined together the DNA from each of the 46 chromosomes found in a single cell, it would measure between 4 and 5 metres! The other surprise was that the total number of genes required for specifying a human is between 25,000-30,000. This is much lower than the figure predicted by scientists as many predicted they would find between 100, ,000. Also, protein coding genes make up only 2% of the total DNA. So, we all contain two copies of each chromosome, and as a result, two copies of each gene. The two copies of each gene are not necessarily identical in their base sequence (or the proteins they encode) and we refer to them as alleles. This highlights another important property of genetic material- it must have the capacity to mutate and generate new versions of genes. Mutation results in changes to the base sequence in DNA, and in some cases this will change the amino acid sequence in the protein it encodes. Mutations in DNA can arise from a number of processes including, errors during DNA replication, or exposure to mutagenic agents such as chemicals, or ionizing radiation. Is there much genetic variation in the human population? Yes there is, look around the classroom (and even your own family), you will see good evidence for this- variation in hair and eye colour, height, shape, and specific facial features. This all results from differences in the particular combination of genes passed down to us from our parents. And that s just the variation we can see with the naked eye! Each one of us is genetically unique. In fact, unless you have an identical twin you can be confident that no one in the past, present or future, will contain exactly the same combination of DNA sequences that you have inherited (Figure 3).
4 Figure 3 The 23 pairs of chromosomes from a human female (a) and a male (b) Mutation is essential for generating variation, producing new genes that will give rise to new proteins which are potentially more efficient than the parental ones and which allow organisms to adapt to an ever changing environment. This principle applies to all organisms, including humans. Unfortunately, not all mutations are beneficial, and some have quite the opposite effect. Some common diseases result when an individual inherits two copies of a defective gene, these are known as recessive. This situation arises when both parents contain one functional copy of a gene and a second defective copy (they are termed heterozygous carriers ), and there is a 25% chance that any of their children will inherit two defective genes. Common examples of this are the defective genes that result in cystic fibrosis and sickle cell anaemia. In other diseases the inheritance of just one defective gene copy is sufficient to give rise to the disease, and these are termed dominant. A common example of this is Marfan s Syndrome. Other diseases are conditioned by genes located on the sex-determining chromosomes and are much more common in males than females. Many diseases are not conditioned by single genes, but by many (they are polygenic ). However, technological advances will soon enable us to determine complete genetic profiles of individuals, and the likelihood of developing particular diseases. What are the ethical issues that arise from a greater understanding of human genetics? So each of us is genetically unique, and today our genes can be analysed at the molecular level to create a genetic profile of any individual. This raises a number of significant ethical issues: What are the implications of being able to determine an individuals genetic makeup? Who should have access to this information? How should the information be used? Technological advances have given us the ability to determine the unique genetic profile of individuals. It is possible to determine the order of bases in the 6 billion base pairs of chromosomal DNA in any individual and determine whether they contain genes that are likely to affect their physical or mental health. This type of analysis does, or will have, significant applications in medicine, paternity testing, the screening of embryos, in obtaining insurance, and in forensic science. As scientists continue to make rapid advances in this field, it is important that all of us consider the implications of the technology. What are the ethical implications that these advances will have for us as individuals, and as a society?
5 Governments realise the importance of guidelines to ensure this knowledge is obtained in a legal and ethical way and that the information obtained will not harm or disadvantage individuals. An example of this is a Code of Practice and Guidance on Genetic Paternity testing Services. Several Government committees have been established to ensure that as scientific advances are made, the potential for discrimination against individuals is minimised. For example the Genetics and Insurance Committee was formed to examine whether genetic testing would allow insurance companies to discriminate against individuals at greater risk of developing a genetically inherited disease. The Government has also introduced new laws such as The Human Fertilisation and Embryology Act (1990) to ensure scientific research is carried out according to strict guidelines and ethical codes of conduct. It has been a struggle for the ethical and legal guidelines to keep pace with scientific advances in the field of human genetics. This is partly because of the consultation processes that have to be undertaken before Government guidelines and Laws can be produced. The Committees set up by Government listen to many different views before they produce guidelines and laws. These include the views of scientists, MPs, industries who may be stakeholders in the new technologies, pressure or focus groups and most importantly the views of the public- that includes you! If we think it is important the Government listens to our views, we have to be able to express and record them so that they can be heard. But most importantly, we have to start to use the information and the scientific facts that are available to form our own opinion of what we consider to be- Acceptable scientific research An acceptable way of using the scientific knowledge In this workshop we have two major objectives. Firstly we will learn more about DNA, genes and human genetics. We will also use group work based around different scenarios that will enable us to consider the ethical implications raised by our ability to determine genetic profiles of individuals. We will begin to: Consider our own opinions and views. Listen to, consider, and take into account the views of others. Develop skills that will allow us to record our views. Develop confidence in expressing our views to others. Determine whether we feel it is important that our views are listened to. Dr Colwyn Thomas School of Biological Sciences, University of East Anglia Norwich NR4 7TJ Dr Laura Bowater School of Medicine, Health Policy and Practice University of East Anglia Norwich NR4 7TJ
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