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INTRODUCTION TO GENETICS IN HUMAN AND ANIMALS:
The unifying topics of this course are how genes and their interactions either with other genes or with environment make us what w e are. When these interactions breaks down genetic diseases may result and it is through these genetics mistakes that we are able to work out what happens in the normal situation. There are many ways in which the study of human genetics differs from that of animals. First of all it is directly relevant to us as individuals, as parents and as decision-makers. Secondly the experimentation in human is limited, which involves enormous amount of detailed observational data are available. Most topics in this essay relate to things we do understand because of some diseases, but much has also been learnt from scientific experiment.
Genetics are the essence of life they are what make up you and your traits and everything about you. They are what connect you and your parents. You inherit all of your traits from each of your parents. They pass them to you from there chromosomes which have the genes on them. Genetics can be helpful in many ways such as in gene therapy you can know if your child will have genetic disorder and also in genetic engineering you can make it so plants are immune to diseases.
Humans and animals genetics are a complex subject which is studied by a variety of techniques which evolved rapidly over the pass years. This essay covers the reproduction of humans and animals using artificial methods (i.e. IVF and embryo transplantation), the patenting of DNA in human and animal. It also covers areas of cloning, genetics screening gene therapy and transfer of genes from one species to another.
The essay covers brief explanation of various topics on application of process today and the possibilities of its future applications. It also deals with ethics of the application and the positive and negative views.
THE REPRODUCTION OF HUMANS AND ANIMALS USING ARTIFICIALMETHODS :( i.e. IVF and EMBRYO TRANSPLANTATION).
Definition and brief history of in vitro fertilization
The history of In Vitro Fertilization (IVF) and embryo transfer (ET) dates back as early as the 1890s when Walter Heape a professor and physician at the University of Cambridge, England, who had been conducting research on reproduction in a number of animal species, reported the first known case of embryo transplantation in rabbits, long before the applications to human fertility were even suggested.
"Conception in a watch glass: The ‘Brave New World' of Aldous Huxley may be nearer realization. Pincus and Enzmann have started one step earlier with the rabbit, isolating an ovum, fertilizing it in a watch glass and reimplanting it in a
Doe other than the one which furnished the acolyte and have thus successfully inaugurated pregnancy in the unmated animal. If such an accomplishment with rabbits were to be duplicated in the human being, we should in the words of ‘flaming youth' be ‘going places.'"
However, it was not until 1959 that indisputable evidence of IVF was obtained by Chang (Chang M. 1959, Nature 184:466) who was the first to achieve births in a mammal (a rabbit) by IVF. The newly-ovulated eggs were fertilized, in vitro by incubation with capacitated sperm in a small Carrel flask for 4 hours, thus opening the way to assisted procreation.
Professionals in the fields of microscopy, embryology, and anatomy laid the foundations for future achievements. The recent rapid growth of IVF-ET and related techniques worldwide are further supported by the social and scientific climate which favors their continuation.
Through the years numerous modifications have been made in the development of IVF-ET in humans: refinement of fertilization and embryo culture media; earlier transfer of the embryo; improvements in equipment; use of a reduced number of spermatozoa in the fertilization dish and embryo biopsy among others.
I N T R O D U C T I O N
The study of biology was radically transformed by the discovery in 1953 of the
Structure of DNA, this is the genetic material of living organisms. Since then,
Scientists have made considerable advances in understanding how DNA works, and
How differences in DNA lead to differences between people. In 1990, the Human Genome Project was established to co-ordinate research that aimed to identify all the genes in human DNA, and to determine the order of the three billion chemical base pairs that make up human DNA. In 2001, the draft map of the human
genome was published, which at least partially identified the majority of the estimated 30,000-40,000 human genes. Many of these genes play a role in human diseases and disorders. Their identification may be a first step in the development of new diagnostic tests and treatments. Research in the rapidly expanding field of genomics aims to discover the biological function of particular genes, and how sets of genes and proteins work together in health and disease. Research is also focusing on identifying and understanding the proteins produced by the genes.
Research into the sequence of the human genome has been undertaken jointly by publicly-funded bodies such as universities, charities, foundations and research institutes, and by privately-funded industrial organisations. Two versions of the map of the human genome Sequence were published by the two communities of researchers, the data from the publicly-funded research having been incorporated into the privately-funded version.1 The public sector project was conducted against the background of a strong commitment to the public sharing of, and access to data. All publicly-funded data regarding the draft sequence were placed on public databases as they were generated each day. In contrast, industry has
generally treated DNA sequence data as confidential.
The protection of knowledge about human genes has primarily been achieved through the patent system, though other devices such as trade secrecy and confidentiality have also played a role.2 The patent system is a long-established method of encouraging people to develop new and useful objects by ensuring that they are able to capitalise on their inventions. A patent confers on the inventor an exclusive right for a limited period of time (usually 20 years) to
prevent others from exploiting the invention. Patents have been used for over a century to protect a wide range of inventions including new medicines, new materials and new machines. Naturally-occurring phenomena such as electricity or wild species of plants or animals are not Regarded as inventions but as discoveries and thus are not eligible to be patented.
Proteins, genes and DNA
Genes are discrete segments of DNA molecules that contain the information necessary for producing specific proteins. DNA is made up of a string of units called nucleotides. The main component of these nucleotides is bases, which are arranged in a specific sequence. There are four different bases in DNA: adenine (A), thymine (T), cytosine (C), and guanine (G).
These bases are bonded together in pairs, A with T and C with G, to make the DNA double helix. Genes can range in size from fewer than 100 base pairs to several million base pairs and are separated from one another by spacer DNA. The base sequence is the crucial feature of the gene.
It is this sequence that carries the genetic information essential for the synthesis of an RNA molecule that may subsequently direct the synthesis of a protein molecule or may itself be functional in the cell. This process is called gene expression; it has two stages. The first stage in gene expression is transcription (the process by which the gene's DNA sequence is copied into RNA) and the second stage is translation (the process by which RNA directs the Synthesis of a protein). Proteins are composed of amino acids and are the molecules that carry out the work of the cell. All the DNA in an organism is called the genome.
Background to the current debate
Chemical compounds including medicines, chemical processes such as the polymerase chain reaction (PCR) medical devices such as the diagnostic test for hepatitis ‘C' have been the subject of patents for some time. Living organisms have also been the subject patents.
The modification of living organisms through genetic engineering in the 1970s and 1980s opened up new possibilities for the development of novel products and processes. By Inserting foreign or synthetic genes directly into a bacterium, scientists were able to contemplate the creation of new drugs based on human genes, new crops and transgenic animals with new or enhanced properties.
Such developments rapidly led to an appreciation of the commercial possibilities arising from genetic modification and the advantages of protecting developments through the application of the patent system. Several hundred small biotechnology companies were established during the late 1970s and 1980s in the US to develop and apply the new genetic technologies. Many were founded within universities by entrepreneurial academics and later ‘spun out' into the industrial sector. These developments in the life sciences, which were mirrored in other technologies, eroded the relatively clear divide between the publicly funded sector of universities, research institutes and foundations, and industry. In 1980, the Bayh-Dole Act was passed in the US, which allowed universities and other public institutes and their employees to seek patent protection for their inventions and retain the royalties.
INTRODUCTION OF PATENTING:
WHAT IS PATENTING?
Patents are exclusive rights granted for a limited period of time by states through their legal systems to inventors to prevent others from exploiting the patent holder's invention. Patent applications contain claims which set out the precise nature of the protection. The commercial exploitation of something within the scope of the claim of a patent that has been granted, without the authorisation of the owner of the patent, is called infringement. Patent claims are normally drafted to ensure that they cover more than exact duplication of the inventor's work. Owners of patents will often themselves exploit commercially the inventions they have patented (for example, by manufacturing a medicine), but possession of a patent alone does not require this. It is possible to have a patent but not to enforce or use it. Many patents are also
Licensed by the owner to other parties for commercial use. A common misconception is that a patent gives an inventor an absolute right to exploit the invention. It does not. Exploitation will depend on whether others have patents which overlap with the subject matter of the invention, and will be subject to other existing laws, such as those concerning health and safety
Patents and DNA
Are there different types of patent?
Patents can be divided into three categories, though these categories are not formally distinguished in the patent system. A product patent is a patent on the product itself. The term ‘product' normally means a chemical or biological entity, substance or composition (as distinct from a device or electrical circuit). A patent that asserts rights over a product itself covers all uses of that product.1 A process patent is a patent on a method or process. This covers a process, and may also include what is directly produced from the process. If a product is made by another process, not covered by the patent, it does not infringe it. A use patent is a patent on the use of the product for a specific purpose; only the specified use is covered.2 For example, in relation to a particular pharmaceutical product, a product patent would cover the active ingredient, further product patents may cover particular formulations, process patents would cover making the active ingredient or formulation, and use patents would cover the use of the drug for a specific medical indication. An important feature of product patents is that they extend to new uses of the invention that developed subsequently, even if these uses were not anticipated or predicted by the owner of the patent.
What types of patent can include assert property rights over DNA sequences?
Of the three main kinds of patent, product, process and use patents, only product patents can assert rights over DNA sequences themselves. Use patents only extend to the use of the sequence. In practice, use patents may also restrict access to the DNA sequence itself.
INTRODUCTION OF CLONING HUMAN AND ANIMALS:
In this essay an overview of the history of animal and human cloning is given, starting as early as the year 1885 and ending with events that have occurred within the last decade. The cloning of Dolly the sheep, being respectively the most famous cloning event, is a significant portion of the essay. The less publicized clones that eventually lead to Dolly are briefly reviewed to show the long path to Dolly's birth. Human cloning, having only a few serious but still not reliable cases reported within the last decade, is also one of the main topics of this essay.
Cloning has long been thought of as a science only used to create an interesting plot in science fiction novels; however, in recent decades cloning has become a reality, maybe not quite yet in humans but it has been successful in animals and human cloning may not lie too far in the future. Major advances were made in cloning starting in the 1970s and cloning has become a more practical science. The cloning of the first mammal, Dolly the sheep, in 1997 was the event that made the world aware of this new science. However, many people probably do not know that the first instance of cloning dates back to over a hundred years ago in 1885 with the cloning of a sea urchin. Today, many different types of animals are being cloned and some scientists propose cloning as a type of immortality (Read). Ideas such as the use of cloning as a means of immortality are modern ideas and cloning as a whole is fairly modern compared to other sciences, but in its short time it has developed a rich history. “Science in truth is a deeply historical, inescapably collective pursuit that has unfolded throughout human history” (Wilmut, Campbell, and Tudge 77).
Cloning before the 1990s was a science not well known among the public because major successes in this field involved non-mammalian animals; although these successes were far from the public interest of human cloning, they are still crucial to the development of mammalian cloning. The first successful cloning was that of a sea urchin by Hans Adolf Edward Dreisch in 1885. The method of cloning used by Dreisch is embryo twinning, a cloning which occurs naturally when a mammal gives birth to twins. He separated the two-celled sea urchin embryo by shaking it until it split into two separate cells which then each grew into an independent organism. The scientist Hans Spemann, director of the Kaiser Wilhelm Institute of Biology in Berlin, also used embryo twinning to clone a salamander in 1902. This time the organism was more complex (it had a backbone) and the cells of the embryo were much harder to split; the cells could not be separated by shaking them. Spemann was able to split the cells by creating a noose out of a strand of baby hair. The cloning was successful in this early stage of the embryo but when tried in a more advanced embryo the cloning was not successful (The University of Utah). Although Dolly is the first mammal to be cloned using the process of nuclear transfer, there were any animals cloned before her using the same process. In 1952, the scientists Robert Briggs and Thomas King successfully cloned a common American frog. They did this through nuclear transfer; they removed the nucleus from a tadpole embryo and placed it in a recipient frog egg cell that had had its nucleus removed, a process called enucleation (The University of Utah). Out of 197 reconstructed embryos, 104 began development, 35 became embryos, and 27 grew into tadpoles (Wilmut, Campbell, and Tudge 92). In 1958, scientist John Gurdon cloned the African clawed frog using nuclei from tadpole intestinal cells, meaning using cells that were differentiated and past the embryo stage of life (94). Derek Bromhall then applied the process of Royal 3
Nuclear transfer to the rabbit, a mammalian organism whose cells are smaller and more complex than those of a salamander or frog, in 1975. He was able to develop an advanced embryo after a few days but not yet an entire organism (The University of Utah). In the scientific journal Nature on March 1985 Steen Willadsen announced his successful cloning of sheep by nuclear transfer; this only differs from the Dolly cloning in the age of the nucleus used (Wilmut, Campbell, and Tudge 151). Nuclear transfer was then used in a larger mammal, the cow, by scientists Neal First, Randal Prather, and Willard Eyestone (The University of Utah).
These calves, named Fusion and Copy, were cloned still using only embryonic nuclei. In 1996, shortly before the birth of Dolly, the same scientists that cloned Dolly, Wilmut and Campbell, cloned sheep from cultured mammalian cells instead of using donor cells from a developing embryo (The University of Utah). The most famous cloning event in history may be the cloning of the first mammal, Dolly the sheep; this cloning was much more complicated than that done by Hans Spemann and it helped launch the modern cloning age. Dolly was born in 1996 after having been successfully cloned at the Roslin Institute in Scotland by the scientists Keith Campbell and Ian Wilmut (The University of Utah). Her existence was not announced to the world until March 1997 in the science journal Nature (Wilmut, Campbell, and Tudge 1). Ian Wilmut stresses that Dolly was more important than other clones at that time because “she was the first animal of any kind ever to be created from cultured, differentiated cells taken from an adult” (232). Many, somewhat skeptical of the success of the cloning, made dire predictions about Dolly; some thought she would be sterile and one American newspaper announced that Dolly was a carnivore that ate her flock-mates (1). In reality, Dolly turned out to be an ordinary sheep. The only problem that could take away from this success was in 1999 when structures at the end of her chromosomes known Royal 4
AUGEMENT FOR AND AGAINST CLONING:
While stem-cell research wins majority support in this country, cloning is another matter:
Most Americans say it should be illegal - for animals, for humans, and even if it could
Produce medical breakthrough .Six in 10 say cloning animals should be illegal in the United States. Six in 10 oppose “therapeutic cloning,” the cloning of a human embryo to produce medical treatments. And 87 percent say it should be against the law to produce a child through cloning. Most are undeterred, moreover, by policies elsewhere. Told that countries such as England allow therapeutic human cloning, more than eight in 10 Americans say it makes difference in their view. This poll summarized two sides of the debate on cloning. For both animal and therapeutic Cloning, supporters say medical breakthroughs could result. Opponents of animal cloning say it's morally wrong and may produce offspring with genetic abnormalities; opponents of therapeutic cloning say it could lead to the creation of a cloned person. These arguments trump the suggestion that agricultural or medical advances may result.
RELIGION - Religious beliefs fuel much of the opposition: Those who oppose animal,
Human and therapeutic cloning are most apt to cite their religious beliefs as the main
factor in their opinion. In contrast, those who support cloning are most likely to cite their
education as having the most influence on their view. Evangelical Protestants are among the most likely to oppose all cloning, while those who profess no religion are among the most likely to support it. Non-evangelical Protestants are a bit more apt to support all cloning than the rest of the public. Catholics closely resemble the population at large.
GENDER GAP - Men and women differ markedly on the issue. Men are 24 points more
likely than women are to support animal cloning - indeed men divide evenly on the
question, while women oppose it by nearly 3-1. And men are 14 points more likely than
women to favor human cloning for medical purposes.
Higher-income Americans are far more likely to favor legalizing cloning than are low-income
people (a majority of those with an income over $100,000 support animal and
therapeutic cloning); and better-educated Americans are more supportive of cloning than
are lower-educated people.
Animal Cloning Human Cloning Therapeutic Cloning
Legal IllegalLegal Illegal Legal Illegal
All 37% 59% 11% 87% 33% 63%
Men 49 47 16 82 41 56
Women 25 71 6 93 27 70
<$25k 17 81 8 92 23 75
$100k+ 64 34 20 80 55 44
Protestants 19 79 3 95 18 79
Catholics 36 61 8 91 32 65
Protestants 43 54 15 83 39 53
No religion 55 40 22 77 53 46
Human cloning should be banned. When the first successful clone (Dolly the
Sheep) was announced to have survived, everyone went haywire. Will cloning
Animals be the next stepping‐stone going towards human cloning? Many would
assume that in time, human cloning would be possible, but due to animal
experimentation in cloning on animals, there can be some side affects to cloning.
Would someone expect two identical people to act just like each other and think the
same way? Should cloning be available to normal people? If the answer is no, then
most must think that cloning is not beneficial to human survival. Cloning excessively
could lead to overpopulation of people or animals. It is very unlikely that the clone
and the original will be alike (in personality).
Some clones are more prone to suffering from diseases than animals that are not clones.Cloning animals excessively can lead to grave animal suffering and it can lead
to excess animals on the streets (Mott)." Many people believe that animal cloning
can lead to overpopulation, and the same could apply if we were to clone humans.
Cloned cattle cost about six times as much money as opposed to the cost of normal
farm animals (Calamai). This states that cloning is pricey, and cloning just for the
sake of another excess animal/human in the world is wasteful and insignificant.
"There are millions of dogs and cats in shelters waiting to be adopted, looking for
responsible owners and loving homes (Braun)." If cloning becomes easier to pursue,
then even more animals will have to be euthanized in shelters each year. Even more
animals will be in shelters if cloning progresses (Braun). If cloning becomes
available to whoever has enough money to pay for the procedure, which can cause
overpopulation in animals or humans, if it continually progresses “You may get a cat that looks the same but the chances are it will not be the same animal socially because those things involve upbringing and environment (Braun)." This states that even if an animal is cloned and it looks exactly like the original and has the same DNA, it is not likely that the animal will act the same way as the original. Though the owners of Lancelot Encore, a clone of a deceased Labrador, say that he acts just like their dog, it is hard to tell what personality traits the clones can inherit from the originals (Marx). Even two identically cloned moose did not have the same result when racing each other and other moose. One of them placed in third, and the other placed in seventh, even though they were genetic copies of each other and exactly the same (Hutchinson). Though they are technically the same, how each clone is raised can affect the outcomes of their abilities. Even though two clones look alike, their abilities cannot be altered to someone's preferences. When cloning, it is impossible to tell how long the clones will survive."Indeed, the technology is so new that it is still overwhelmingly unsuccessful. Its
Success rate, at best, is one live birth for every 75 attempts ‐‐ a rate that some
Scientists think suggests a deeper problem with the technology, a problem that
Could adversely affect the long‐term health of cloned animals (Lee)." Though
scientists can predict that the DNA and looks of the clone and the original will be the
same, they cannot predict how their health will affect them, because of being a clone.
Dolly, a cloned sheep, died at the age of 7, and she had arthritis (Beardsley). They
were not able to tell if the fact of her being a clone had to do with such a short
Lifespan, but cloning has gone to extremely high standards when cloning for high
amounts of money. "Roughly 98 percent of cloned animal embryos fail to implant in
the womb or die while developing. Of the few babies that do survive, some die
shortly after birth (Westhusin)." Countless lives are wasted in a process that could
have a much better chance if it were done naturally. When thinking about cloning a
human, some think that they have higher expectations than animals, since they are
expected to act the same as the original human they were cloned from, but they are
subjected to more ailments. You can never attempt to guess how "healthy" a clone
will turn out to be, but in the end, each individual clone is a different case than other
animals/humans and of its original.
Risk and Relationships
To clone one member of a couple to solve infertility would not be instrumental, but would also raise other profound problems. No one knows the psychological effects of discovering one was the twin of one of one's ‘parents', biologically the child of one's grandparents. Would I feel I'm not really me but a ‘copy' of someone else? What would be my relationship to them? Since we have no sure way of knowing in advance, we surely do not have the right knowingly to inflict that risk on another person. Lastly there is the physical risk, in the light of the animal cloning experience. Major pregnancy difficulties are often a feature of cloning in sheep and cattle. Cloned mice have been found to die younger. Much of the basic science of nuclear transfer is still uncertain. No one knows how to guarantee that the cell reprogramming process would not lead to serious abnormalities in the offspring or danger to the mother. To translate such risks into humans would be utterly unethical medically. In each different species, cloning is a first of a kind. No matter what advances were made in animal cloning, it could never be ethically justified to experiment on creating a human clone, due to the unquantifiable risk of serious harm in those first attempts. One cannot ‘put down' a deformed cloned baby the way one might a suffering lamb.
What about Cloned Human Embryos for Research?
But if cloning people is wrong, what about medical applications? The proposal to extract stem cells from cloned embryos to produce genetically matched replacement cells for degenerative diseases (‘therapeutic cloning') now looks very uncertain. It is unlikely the huge numbers of human eggs needed would enable it to be a routine therapy. Uses of cloning in research could throw light on cell and embryo behaviour, fertility and mitochondrial disease. Cloned embryos might be used in research to create stable lines of disease state cells to research motor neurone disease. For some, all embryo research is unethical. But even for those not opposed to using IVF embryos, applications which use cloned embryos raise serious ethical questions. We explore these further in our information sheet ‘Ethical Problems with Cloned Embryo Research'. The sheet ‘Embryonic and Adult Stem Cells: Ethical Dilemmas' examines the wider issues of embryo stem cell research. The increase of scientific possibilities underlines the urgent need to have an enforceable UN ban on reproductive human cloning, for which the Church of Scotland General Assembly called in 1997. Without this in place, the use of cloned embryos for research risks leaves the door open to maverick scientists to abuse the technology for their own ends.
INTRODUCTION TO GENETIC SCREENING IN HUMANS:
Daniel St Johnston
The success of Drosophila melanogasteras a model organism is largely due to the power of forward genetic screens to identify the genes that are involved in a biological process. Traditional screens, such as the Nobel-prize-winning screen for embryonic-patterning mutants, can only identify the earliest phenotype of a mutation. This review describes the ingenious approaches that have been devised to circumvent this problem: modifier screens, for example, have been invaluable for elucidating signal-transduction pathways, whereas clonal screens now make it possible to screen for almost any phenotype in any cell at any stage of development.
The fruitfly Drosophila melanogasterhas been one of the favourite model organisms of geneticists, since Thomas Hunt Morgan decided to use it to investigate the chromosomal theory of inheritance at the beginning of the last century1. Morgan chose Drosophila because it is easy and cheap to rear in the laboratory, has a ten-day generation time and produces many progeny. However, he soon discovered that it has several other advantages for genetic analyses. For example, there is no meiotic recombination in males, and there are only four chromosomes, which can be directly visualized in the giant POLYTENE CHROMOSOMES of the larval salivary gland. Furthermore, its exoskeleton provides a wealth of external features, such as bristles, wing veins and compound eyes, which can be affected by mutations, and for which the resulting mutant phenotypes can be scored simply by looking down the stereomicroscope. This early start has been built on by succeeding generations of drosophilists, who have developed an ever-increasing repertoire of techniques that make Drosophila one of the most tractable multicellular organisms for genetic analysis2. In fact, Drosophilahas only one main drawback, which is that the stocks have to be continuously maintained in the laboratory because it is not possible to freeze them (and successfully revive them afterwards. An unfortunate feature of genetic model organisms is that the easier they are to work with, the worse they are as models for the animal that most funding agencies find most interesting, namely ourselves.
However, Drosophilaprovides a very happy compromise. A surprisingly large number of developmental processes seem to be conserved between flies and vertebrates, even though they diverged at the PROTOSTOME DEUTEROSTOME split ~700 million years ago. To cite two of the more famous examples: the dorsoventral (D/V) axes of the Drosophila and vertebrate embryo are patterned by opposing gradients of Decapentaplegic and Short gastrulation even though the orientation of the axes is reversed; whereas Hedgehog and its vertebrate counterpart, sonic hedgehog have remarkably similar roles in limb patterning in both systems. The sequencing of the Drosophila genome has now revealed
the true extent of these similarities.
Traditional genetic screens
Although the early drosophilists isolated many visible mutations, these were all spontaneous alleles from natural populations, and genetic screens only became
Possible once better ways to generate mutations were developed. The most efficient method to do this is to feed flies ethyl methane sulphonate (EMS), which induces point mutations, following the protocol described by Lewis and Bacher in 1968.
This is the most commonly used mutagen in Drosophila because it is easy to administer and causes the highest frequency of mutations. It mainly induces single-base changes (point mutations), which disrupt gene function by causing missense or nonsense mutations, and the frequency at which a gene can be mutated therefore depends on the size of the coding regions and the number of crucial amino acids that it contains repaired yet.
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R E V I E W S
A chromosome with one or more inverted segments that suppress recombination. They are used as genetic tools because they allow lethal mutations to be maintained without selection.MATERNAL-EFFECT MUTATION Homozygous-viable mutation that causes little or no phenotype in the mutant mothers, but leads to the development of abnormal offspring.
Until 1980, most drosophilists were still preoccupied with understanding the nature of the gene, and most mutagenesis studies were designed to discover new alleles of existing genes or to find out how many genes there were in a particular region of the genome. This all changed when Christiane Nüsslein-Volhard and Eric Wieschaus published their Nobel-prize-winning Nature paper on mutations that affect the patterning of the embryo. This work was revolutionary, because it was the first mutagenesis in any multicellular organism that attempted to find most or all of the mutations that affect a given process, and because it was one of the first screens for phenotypes in the embryo rather than the adult, which allowed them to identify null or strong mutations in most of the essential patterning genes that are used throughout development. As Peter Lawrence pointed out, half of the talks at the Drosophila meeting in Crete ten years later were about genes that were identified in this screen, which gives some idea of the impact of the paper. Two features of Drosophila development had a profound effect on the success of the screen. First, because Drosophila has an exoskeleton, the larval cuticle provides an exquisite readout of the patterning of the embryo. Second, Drosophilaembryogenesis has evolved to occur as rapidly as possible, and the mother therefore loads the egg with most of the products of genes that do not need to be transcribed in a precise pattern in the embryo. This means that, in contrast to other organisms, very few mutations block embryonic
development at early stages and most mutants in housekeeping genes complete embryogenesis and secrete a normal cuticle. The screen was therefore very
efficient at identifying the transcription factors and signalling molecules that generate positional information in the embryo. No genetic screen can find everything, and it is worth considering what sort of genes could not be identified in the famous Heidelberg screen. This indicated that they must be regulated by maternal determinants that are deposited in the egg. To find these factors, the Nüsslein-Volhard lab, and Eric Wieschaus and Trudi Schüpbach, carried out saturation
mutageneses for maternal-effect mutations, which identified many of the genes that are involved in generating the four maternal signals that define the two main axes of the embryo second class of genes that were missed in the screen comprises those that have specific roles in the patterning of internal structures, such as the nervous system, because it is obviously impossible to identify mutants that have no effect on the structure that is being screened.
GENE THERAPY - THE GREAT DEBATE!
GENE THERAPY is important - it may revolutionise medicine during the next ten years and has great potential for the biotechnology industry. Many people think that there are associated ethical issues. Europe needs to address the evolving questions, to join the national and international debate, and to formulate a European response and perspective. A scientific expert group supported by the European Commission assessed some of the issues associated with this rapidly expanding field.
The Scientific Background
GENES are made of DNA - the code of life. They are made of a sequence of chemicals with the initials A, C, G and T, just like the alphabet makes words and sentences which can be turned into instructions. Everyone inherits genes from their parents and passes them on in turn to their children. Every person's genes are different, and the changes in sequence determine the inherited differences between each of us. Some changes, usually in a single gene, may cause serious diseases (such as CYSTIC FIBROSIS, MUSCULAR DYSTROPHY OR THALASSAEMIA). More often, gene variants interact with the environment to predispose some people to CANCER, or HEART DISEASE, or other common ailments. Today doctors
Can look at a person's DNA using very sensitive new techniques which use as little as one hair root or drop of blood. Our cells are divided into two groups, the somatic cells which make up the working parts of the body, and the germ cells (or sex cells: sperm in men and eggs in women) which pass on genetic material to our children. Every normal somatic cell contains the same coded DNA instructions, even if only some of them are used. Different ones will be active in different parts of the body.
SOMATIC GENE THERAPY
It will only change cells in the body of the person being treated, and not be passed on to Children. Somatic gene therapy can be targeted to, for example, the liver, blood or lungs, to correct a medical problem which already exists and which can be treated by the gene or its protein product, such as an inherited disease or cancer. Sperm and egg cells are different. They are the cells which go to form the individuals of the next generation and pass the genes from both parents to the offspring. They are the GERM CELLS.
GERM CELL GENE THERAPY
would involve the deliberate insertion of a gene into the germ cells, deletion of a gene from them, or alteration of a gene already there. Most people agree that germ line therapy raises serious ethical issues, since changes would be inherited.
What exactly would be done in human somatic gene therapy?
Genetic therapy uses purified preparations of a gene or a fraction of a gene to treat a
disease. This can be done either by correcting the functioning of a cell in which a single gene does not work properly from birth or sometimes by killing a cell which is out of control. Therefore diseases such as cystic fibrosis, diabetes, Parkinson's, Alzheimer's, heart disease and cancer are all targets for somatic gene therapy. Indeed current trials are assessing the safety and 9 success of this kind of treatment in some of these diseases. There are several approaches to the introduction of genetic material into a somatic cell. These include direct injection of the gene into the cell, using a VIRUS to carry a gene into a human cell, or merging it into the cell with a fat particle called a LIPOSOME, or an antibody like protein that can recognise the cell surface. These techniques are in their infancy, but are already being used in trials to attempt to treat several rare inherited diseases such as cystic fibrosis, and some cancers. In some ways, SOMATIC GENE THERAPY involves the delivery of a naturally occurring molecule to the patient and his/her cells. There is an implication therefore that it is likely to be more effective for particular diseases than conventional drugs. Because only somatic cells are receiving the human gene, the treatment will probably have to be repeated, perhaps for the person's lifetime.
Some big questions to ask:
Is it new?
Yes, it is new, because it rests on the scientific techniques developed in the 1980's and
1990's to allow investigation of the structure of DNA, first discovered by Crick and Watson in 1953. There have also been significant advances made in analysis of human genes (The
Global Human Genome Programme). The use of these and other techniques have allowed the
genes and gene disorders to be identified and tracked through families with great accuracy.
The genes, some of which have been identified for the first time using the new techniques,
combine with each other and the environment to make us what we are.
Does it matter?
Yes - because there is great interest in using techniques to introduce normal genes into
Cells in the treatment of literally dozens of diseases, from quite rare ones which for example can cause failure to digest nutrients properly (such as phenylketonuria) to more common
disorders like cancer, AIDS, heart attacks or Alzheimer's disease.
Does that mean that scientists will be interfering with a person's
No, because the new treatments that are proposed are aimed at the somatic cells, and will
Only treat affected cells in the body of the individual patient, such as muscle cells for
muscular dystrophy, whereas germ line gene therapy in humans would be aimed at egg and
sperm cells which control inheritance. This type of therapy is or will be prohibited by most
Won't there be some doctors who will go ahead with germ line gene
therapy, just to see if it can be done - or for money or power? How will
patients be protected?
Any new discovery can be misused. That is precisely why we need a set of rules and
guidelines which ensure practices are used only according to ethical standards agreed upon
after political, scientific and medical discussion. We also need much more public
understanding and informed discussion, since in the long term this is the only insurance
Are there a lot o f new ethical questions related to somatic gene
Most philosophers, doctors, scientists, lawyers and ordinary people (and especially the
patients and their families) think that somatic gene therapy to treat a serious disease is much
needed, and only raises the same sort of ethical issues as in other branches of medicine for
example organ transplantation. However, somatic gene therapy - like any new treatment -
requires a proper assessment of safety and effectiveness, and informed patient consent.
Does somatic gene therapy have anything at all to do with
Not really - but if effective treatment such as somatic gene therapy were to exist for any
Serious inherited disease, parents who know they are at high risk of having children with an
inherited disease may be more willing to have an affected child, because earlier and more
effective treatment should be available.
What about patenting human genes for therapy? Wouldn't this be
the equivalent of patenting life itself?
No, although this is a very controversial issue. Genes from any source, including humans,
are chemicals and can be patented. Patenting involves protection, for a limited time, of the
property rights of an inventor in return for making information about the invention available
to all. The "invention" is defined legally - to be patentable, it must be novel, inventive and
useful.Patents are not granted if the exploitation would be contrary to "order public" or morality.Some patient and public interest groups argue against patenting of human genes on the principle that genes are in every person, belong to all, and their use should not be restricted in any way. However, by establishing an exclusive position, a patent provides an incentive to invest in research and development. Without patent protection, companies would not invest the large amounts of money needed to develop the use of genes and gene products for therapy.
What could the European Parliament do about patenting?
The draft directive of 1988 on the legal protection of biotechnological inventions was
rejected by the European Parliament in March 1995. In December of the same year, the
European Commission adopted a new draft taking into account several objections raised by
the European Parliament, such as the exclusion from patentability of methods of germ line
gene therapy on humans. The proposed directive aims at clarifying the existing national laws
in a uniform manner and ensuring legal certainty throughout the European Union. It would
avoid a proliferation of divergent legislation and case-law that would threaten to fragment the
single market. The European Parliament by and large recognises the need for legislation, and
has started its debate. The adoption of a directive in its present form would improve Europe's
attractiveness for research activities.
Are there already regulations to enforce safe practice for somatic
Yes. There are already harmonised European rules on the use of genes, particularly with
respect to possible release into the environment ("The Release of Genetically Modified
Organisms"). The principles applied to the use of products derived from biotechnology form
the basis for gene therapy. More European wide and specific rules may be needed for gene
therapy to ensure that good practice is maintained throughout Europe.
The marketing authorisations for biotechnology products are granted by the European
Commission only after a thorough evaluation of safety, quality and efficacy according to strict rules and guidelines under the auspices of the European Medicines Evaluation Agency.
In many EU countries clinical trials require approval of the competent national authorities
before they can be conducted and most require Ethics Committee approval at the hospitals
and centres where the trial is carried out. In some countries, gene therapy trials must be
reviewed by another body, a Gene Therapy Advisory Committee before they can begin.
Although most biologists regard them as a fundamental unit of nature there is disagreement as to how to define ‘species'. There are more than 20 species concepts that belong to two main schools of thought, either phylogenetic or non-phylogenetic.
Phylogenetic species are based on some form of reconstruction of the evolutionary history, whereas non-phylogenetic species are based on other factors such as morphological similarities.
For the purposes of this paper, the extent of gene flow between different groups is the important issue. How a species is precisely defined is not so important in this context.
Horizontal gene transfer and transgenes
Minor portions of DNA can naturally transfer between living organisms. Horizontal gene transfer involves the transfer of small amounts of DNA between individuals other than by sexual or asexual reproduction (which is ‘vertical' gene transfer). This section examines the influence of horizontal gene transfer in debates about trans-kingdom gene transfer.
It should be noted that Gene Technology Act 2000 does not include horizontal gene transfer between bacteria in the definition of a genetically modified organism.
Natural gene transfer
Horizontal gene transfer is independent, unidirectional, and occurs commonly in bacteria. Scientists have known for more than 60years that bacteria can acquire naked DNA (DNA that does not have any proteins bound to it) from the environment as genomic or plasmid DNA, or through interaction with bacterial viruses (Avery et al.1944). In addition, agrobacteria are able to add genes to the chromosomes of plants and perhaps even to add genes to animals (including, potentially, humans). Horizontal gene transfer is now considered the most important mechanism for the evolution of new traits in bacteria.
Horizontal gene transfer can occur in organisms other than bacteria. In disease initiation in some plants, the bacterium Agrobacteriumtumefacienstransfers genetic material to the plant, which is incorporated into the chromosome and expresses a range of genes. This process is now commonly used for the artificial transfer of foreign genes expressed in plants. A potential problem is that, although a gene from a eukaryotic cell may be non-coding in a bacterium, it does not mean that it cannot be transferred to other eukaryotic cells where it can code for a protein. This raises ethical questions, because it suggests that there is not complete control over the process.
Some scientists believe that many human genes are the result of horizontal gene transfer from bacteria, while other scientists argue that the putative horizontal gene transfer genes are present in more ancient eukaryotes (nucleated cells) and have been transferred through vertical gene transfer.
Artificially produced transgenes differ from natural genetic variation, because their numbers are increased by humans artifically and transgenes are often modified to allow expression across a broad range of hosts. Inserting a transgene into a chromosome may affect the stability of the genome and thus the probability of horizontal gene transfer. For example, where a transgene decreases the genome's structural stability, it increases the availability of DNA for horizontal gene transfer and recombination. There is less horizontal gene transfer in bacteria with stable genomes than those with less stable ones. This stability can result from the loss of genes responsible for transferring genes (see Silva et al. 2003).
The potential for transgenesis to destabilise the recipient's genome and increase the probability of horizontal gene transfer (Woese 2004) is of concern because of the uncertainty surrounding the spreading of a transgene to nontarget species and causing ecological damage, such as disrupting a biological community. That having been said, it is interesting to note that the human genome has a large amount of DNA of viral origin in the non-coding part of its DNA (see MacPhail 2004). There does not seem to be any evidence as yet about humans being recipients to DNA from prokaryotic and other eukaryotic organisms. The difference in the frequency of HGT by viruses and other organisms is that viruses are parasitic, making use of host replicating and production machinery to produce more viruses, whereas prokaryotic and eukaryotic organisms are not. In summary, gene transfer across kingdoms may be problematic because species from different kingdoms are more distantly related than are species from within the same kingdom. In other words, more distantly related organisms have a shorter shared evolutionary history and therefore the degree and nature of organisation of genome function are very different.
Artificial gene transfer
Gene transfers made by humans using gene technology are not a simple extension of traditional breeding techniques. There is a profound difference in the genetic composition of modified organisms. In traditional breeding, a gene for the desired trait is inherited with 50% of the genome of the parent organism. Thus, the gene remains with other genes that have evolved together in a gene pool, and are more likely to be compatible with one another than they are with genes from a different gene pool. Introducing a foreign gene using gene technology may disrupt the genome's stability — a stability that has taken many generations to stabilise under specific selection pressures. Increased instability of the genome may cause ecological problems as well as problems for the organism itself (Hulsman 2004). The ethical issues associated with these scientific points relate to ecological integrity, animal welfare and the intrinsic value of the organisms involved.
The cognitive framework used when considering gene transfer affects the predicted outcomes of genetic manipulations, and therefore also affects the ethical issues raised. For example, certainty of the outcome of any genetic manipulation is greatest where the transgene's expression is independent of other factors. In contrast, certainty of the outcome decreases where other factors, such as the gene's genetic neighbourhood and external environment, affect the gene's expression. In other words, the level of uncertainty in outcomes of genetic manipulations depends on whether other factors affect the transgene's expression (Hulsman 2004). Therefore, one could encounter ‘surprise' or unexpected outcomes (including no effect), if one were to assume that other factors did not affect the transgene's expression, when in fact they did. Increased uncertainty about the outcome of any genetic manipulation raises ethical issues that would not be raised, if the outcome were certain.
Trans-species gene transfer
Fungi, plants or animals may be genetically manipulated to introduce or enhance some characteristic that already exists within a species. In cases where the characteristic is naturally expressed, a natural process could, in the right conditions, transfer the introduced characteristic to another organism. Trans-species gene transfer, however, involves the movement of genes between different species. For example, using gene technology techniques, genes from a bacterium can be inserted into a plant; this is the case with Bt cotton, where the gene is expressed and provides a defence against insect pests.
It is popularly assumed that the various species and kingdoms are distinct and separate, and that under normal circumstances genes cannot be transferred between them. In this sense, gene transfer between kingdoms may introduce new ethical questions beyond those involved in other forms of genetic modification within kingdoms or genera.
Included within the ethical discussion about trans-species gene transfer are gene transfers between higher levels of taxonomic classification (such as families, classes, orders, phyla and kingdoms), and whether these gene transfers lead to ethical issues in addition to those associated with gene transfers between more closely related organisms.
Particular ethical questions arise where, for example, a human gene is inserted into an animal or crop. The effectiveness of the boundary between species for gene transfer increases as more distantly related species are involved, and the associated ethical issues must be identified. Evolutionary history shows that organisation of cells has become increasingly complex with time (Woese 2004). This complexity results from the increased connectivity between different parts of the genome. The shorter that shared evolutionary history of a gene has with the recipient genome, then the more likely that the gene will disrupt the organisational complexity of the genome thereby decreasing the function of genome and thus its survival value. With increasing connectivity between clusters of genes and within a cluster, the placement of a transgene is crucial for the recipient's fitness.
A transgene is any gene that is transferred from one species to the genome of another. Most species of multicellular organisms are distinct and do not normally transfer genes to one another, whether they are closely or distantly related. The scientific definitions of taxonomic categories, such as species and kingdom, are not fixed and are still subject to scientific debate. However, the vast majority of gene transfers involve organisms that are clearly of different species, irrespective of how species is defined. Although horizontal gene transfer does occur in eukaryotes, it is negligible compared with the number of gene transfers made using biotechnology. In addition, the quality of natural horizontal gene transfer differs from that of artificial gene transfers. For example, horizontal gene transfer includes the transfer of non-coding DNA, or coding DNA that does not confer a selective advantage and so may be lost through genetic drift. The transfer of genes whose expression is affected by neighbouring genes or by environmental conditions is more problematic than the transfer of genes whose expression is not affected by other factors.
Ethical concerns of the public
Clearly, the ethics relating to trans-species gene transfer are of public concern. It is notable that the final Senate report published in November 2000 is titled A Cautionary Tale: Fish Don't Lay Tomatoes. The preface to the Senate report states:
One major area of concern was the gene crossover, sometimes described as transgenic, from one species to another. There was much less concern about wheat genes being used in wheat than bacterial genes being used in wheat, for example.… While there may be genetic exchange between species occurring in nature, genes from fish do not get into tomatoes under normal circumstances (Parliament of Australia 2000, page xii)
The variety of ethical concerns about trans-species gene transfer is also seen in Reflections on the Use of Human Genes in Other Organisms: Ethical, Spiritual and Cultural Dimensions. The benefits of trans-species gene transfer to health and the community are recognised; however, at the same time there is a desire to keep important community values connected to science, and it is recognised that innovations aimed at benefiting the community must be weighed with ethical, spiritual and cultural issues (Forman 2004).
Threats to the integrity of organisms
In the report, most authors are concerned that trans-species manipulation has the potential to threaten deeply held values. For some community groups, transgenic manipulation is a threat to the integrity of the organisms involved, because it ‘blurs the necessary distinctions' of organisms (Moxon 2004). Some groups have a religious basis for maintaining the distinction between species (Jarvis et al 2004). For other groups, the most problematic issue is respect for the uniqueness of people when they are involved in trans-species gene transfer. They argue that ‘the transfer of genes that cause phenotypic (observable) changes so that the organism shows human characteristics is completely unacceptable to many people and is against Christian and Maori spirituality' (Jarvis et al 2004). This concern does not always apply to every possible situation. One paper argues that many aspects of gene manipulation involving people are positive and to be celebrated, and that it is only the manipulation of some genes — master regulatory genes — that should be treated with great caution. Only some manipulations are ‘outside the limits of what is acceptable' (The Nathaniel Centre 2004).
Threats to the intrinsic value of the natural world
Other groups are concerned about the intrinsic value of the natural world and what is seen as the ‘growing contempt of nature … using creatures simply as tools' (Moxon 2004). Some people suggest that the value of organisms should be judged by their closeness to people, and whether there is ‘a right not to be genetically engineered' for ‘the species with which we have close genetic and social relationships' (Wills 2004).
Threats to cultural and social identity
For other groups, the appropriateness of trans-species gene transfer must be related to indigenous knowledge (matauranga Maori) concerning the relationships between people and other forms of life (Durie 2004). At this point, the rights of people become involved. Other groups are also concerned about human rights but in a different way. Some argue that people have a right not to have to eat food that has been genetically modified with genes from another species. This may occur in situations in which a certain proportion of food can be genetically modified without notification being required on the packaging (Carapiet 2004).
Threats to specific communities
The rights and values of specific communitiesare also a concern. Cultural, religious and ethical views should be included when considering trans-species gene transfer, and an exclusively scientific assessment of the risks, benefits and ethics associated with gene transfer should be avoided (Moxon 2004). The Royal Society of New Zealand notes that its code of ethics says that members ‘have a duty to respect the values of communities which may be affected by their work' (Gunn and Tudhope 2004, p31). Maori contributions suggest that transgenic manipulation could constitute a risk to indigenous culture because of indigenous beliefs about the natural world (Durie 2004). In addition, the methodologies usually associated with decision-making processes concerning gene transfer are based on scientific analysis and do not allow other factors, such as cultural and religious beliefs, to be included (Durie 2004).
Potential concerns relating to trans-species gene transfer
Qualitative research on attitudes to gene technology shows that public concerns relate not only to the physical risk and health matters associated with gene technology, but also exist at an existential level concerning ontology (the nature of things), including the meaning of human nature and the presence of some fundamental order in the natural world. The argument has been expressed in the following way:
- People often have a sense of given order that is radically challenged by the possibilities inherent in gene technology and, especially, by the novelty of trans-kingdom gene transfer.
- Despite this, there is also a feeling that, in certain circumstances, some artificial modifications to genes may be justified, provided the purposes are the right ones.
- There is also a fair degree of cynicism and fatalism that such conditions are unlikely to be met and that more dramatic and less justifiable genetic changes will occur (Deane-Drummond et al 2002).