Man or Mouse
Uses of, and Problems with, Genetically Modified Animals
If promises from those involved in their creation are to be believed, the contribution of GM animals to human life will rival that of the wheel. Manipulating the genomes of 'imperfect' animals will lead to a complete understanding of genetics and cell biology; drugs to cure all diseases; simple and reliable test protocols to determine which chemicals, drugs and foodstuffs are safe and which dangerous and in what amounts; an unlimited supply of animal organs for human transplant with no problems of rejection; animals that can act as 'drug factories,' churning out huge amounts of effective drugs in their milk.
We look at each of these areas here, but pay particular attention to GM animals in biomedical research, which constitutes the biggest area by far in which they are used.
1. Human disease
"With the exception of basic genetic mechanisms, the mouse is a relatively poor model for the human."
As previously mentioned, animal models of human diseases have been around for several decades. Their use declined substantially for more than ten years, arguably as scientists realised their futility, until the advent of transgenic technology enabled them to utilise extraordinary new methods to search for those elusive 'more human-like' models that promised fame and fortune. Since that time, countless GM animals have been created and offered to science as putative models of a wide range of human diseases. The difficulty for those scientists trying to make sense of all this... is that it's just not that simple.
All diseases have a genetic component to some degree. Some diseases are 'caused' largely by external factors such as diet, lifestyle and pollution, in which our genes merely predispose us to a degree of resistance or susceptibility. With lung cancer, for example, one individual could smoke heavily into old age yet never suffer significantly, whereas another non-smoker could contract the disease early in life from passive exposure. Other diseases have a firm genetic cause: sometimes only one gene is responsible, sometimes several. Some identical genes and mutations can cause disease in some individuals but not in others.
It's also important to bear in mind here that humans have 23 pairs of chromosomes in each of their cells; we have two copies of each of our genes, one is passed from the mother and the other from the father. Sometimes, a faulty gene inherited from one parent will be of no consequence providing we have a normal copy from the other; here, the faulty gene is termed 'recessive'. Only when an individual has two copies of the faulty gene is there an effect. But in some cases, certain mutations can be 'dominant', meaning that if we inherit one faulty copy we also get the disease, despite the presence of a normal copy.
GM animals have been used to model a number of human diseases from each of these categories. As an introduction to their use and their relevance to the human diseases for which they are models, a brief summary of some of the most interesting is given here. We begin with the genetically 'simple' and perhaps the longest running GM disease investigation for which there is plentiful data: cystic fibrosis.
As the most common inherited fatal disease in much of the world, affecting 1 in every 2500 children, cystic fibrosis (CF) has always attracted a great deal of research attention. Its cause in humans has been known since the 1980s when in vitro research culminated in the discovery of the gene responsible, known as CFTR. This gene encodes a protein that functions as a 'channel' in and out of various cells of the body. When faulty, this gene gives rise to a channel that doesn't form properly and this results in the build up of very thick mucus - predominantly in the lungs and pancreas but also sometimes in the liver. Pancreatic problems affect most CF sufferers but by far the main cause of death is chronic lung infection, rooted in the sticky secretions that form a breeding ground for harmful bacteria.
Instead of proceeding at full pace with human-based research, scientists turned to mice and began to look for a similar gene to see if, when mutated, it caused anything resembling human CF. This persistence with animal use occurred despite a previous record of abject failure with non-GM CF animal models. Despite huge expense and effort centred around the injection of bacteria into these 'conventional' animals' lungs and the induction of allergic airway disease, the project consistently failed to provide any useful information.
Presumably the hope had been, if successful results were forthcoming, to use the GM model to probe further the progress of the disease and also to test potential treatments and cures. A gene was finally found that was 78% similar to the human CFTR gene, and this was the signal to create transgenic mice with mutations. Because CF is a recessive condition, mice had to be engineered and bred with two mutant CFTR genes, termed (-/-) mice.
Some observations and excerpts from the scientific literature reveal the true extent of the disaster that has unfolded since this time. It is important to keep in mind the progression of CF in human beings:95% of sufferers die from lung infections; pancreas disorders affect 85%, and liver disorders up to 43%. Intestinal obstruction is not a human factor:
- CFTR (-/-) mice 'do not have the mucus-clogged lungs and persistent lung infections that plague human CF sufferers. That could be because the lungs of mice are fundamentally different from those of humans - they have fewer mucus-secreting glands and cells overall ... our CFTR mice die early in life of gastrointestinal obstruction, and not from pulmonary [lung] infections.'
- 'Symptoms of the CF mice are hardly identical to those of human CF... there are just too many subtle physiological differences between the two species.'
Different teams began to argue about the merits of their own particular mice. None of them, however, could argue that its model had been a success:
- 'The apparent differences in [the mouse models] underscore the complexities of modelling human diseases in animals.'
- In all mouse models pancreatic blockages, if they occurred at all, did so at a late stage, only occasionally and, were much less severe than the human equivalent.[39,42,43]
- Many CF mice suffer from intestinal blockages (not seen in humans), and die in early life from them.[43-46]
- Almost all male CF sufferers are infertile due to reproductive tract problems: there is no such evidence in the mouse models.[39,47]
The unavoidable conclusion is that animal models of CF have been an unqualified failure. This was always going to be the case: chronic lung infections, brought about by thick mucus secreted by the serous glands, kill human CF patients ... and mice don't have these. Their lungs are different, their cells are different and their gene expression is different. [48-50]
What use is an animal model of CF in which many animals die of unrelated complications before lung and pancreatic problems have a chance to manifest, and where those animals that survive don't suffer the pancreatic problems and lung infections that are the main targets of the disease in humans anyway? [51-54]
The history of CF research had been an immensely promising list of achievements without using animals. Autopsies, clinical observation and in vitro studies were responsible for revealing the biochemical nature of the disease, its mechanisms, the pancreatic problems and the development of diagnostic tests.[55-58] Yet still researchers persisted with and obsessed about an animal model. Even in the face of the information above and with successful laboratory-based culture of human CF-affected cells a reality, scientists are still consuming valuable funds and time using animals, presumably out of habit, hubris and intransigence... and it still isn't working. Studies in mice showed that an alternative channel to CFTR could compensate for it when it is 'knocked out,' resulting in healthier tissue. In human tissue, this is not the case. [59-61] In mice, the activity of curcurmin (a component of the spice turmeric) can correct CF defects, a finding that caused great excitement but that was not replicated in human cell cultures.[62,63] 'Gene therapy' trials that were successful in mice [64,65] have led to no less than 29 failed human trials.
Evidence that scientists are moving away from transgenic mice CF research might be encouraging, if that movement wasn't towards other animal models. The mouse may have proved to be futile to many researchers, but it seems their problem is not with the animal model; it's with the species. Cue efforts to investigate CFTR activity in sheep, ferrets, and non-human primates.[67-69] The inability of many scientists to act upon the facts in front of them is astounding.
The contribution of non-animal research, however, continues, despite attracting less funding than animal models. This is evidenced by the development of effective treatments to protect against killer infections and thin the lung mucus[71-73] such as dietary measures, physiotherapy and infection control, that have increased life expectancy by decades to over 40 years.
Parkinson's Disease (PD) currently affects 1 in 500 people in the UK, representing 120,000 people in total or about 1-2% of the population above the age of 65. It manifests as tremors, muscular stiffness and slowness of movement, and is characterised by the loss of cells in a part of the brain called the substantia nigra that produces a chemical known as dopamine, which is involved in the transmission of signals between nerve cells (neurons).
The causes and progression of PD are poorly understood, but there are thought to be genetic and environmental factors involved. In addition to loss of cells producing dopamine (dopaminergic or 'DA' neurons), a hallmark of the disease is the presence of objects called 'Lewy Bodies' in those DA neurons that do survive. These Lewy Bodies are primarily composed of three proteins, called alpha-synuclein, ubiquitin and parkin.
Genetic studies of human populations and PD sufferers have revealed that mutations in the genes that produce these three proteins, amongst a number of other candidate genes, can actually cause the disease.[76-83] Naturally, since these human-based discoveries, transgenic knock-out mice have been created with defects in these genes based on the assumption that they would reveal a whole host of useful information about human PD.
Rather predictably though, they have served to confound the situation, producing results that are unclear, inconsistent and contradictory to human PD:
- In mice, a lack of alpha-synuclein results in neither the Parkinsonian phenotype nor alterations in DA pathways. They do not exhibit any obvious pathological features, and their development is normal.
- Transgenic mice overexpressing either normal or mutant alpha-synuclein have generated inconsistent results.[85-87]
- Recent gene targeting strategies have generated several mouse lines with mutations in the DA system, which serve only to highlight the crudeness of this approach. Mice lacking genes involved in DA production die at a late embryonic stage or shortly after birth.[88,89]
- Transgenic rats with altered alpha-synuclein expression have been created that did show substantial dopamine loss. However, their motor behaviour was only marginally affected, or not affected at all.
- Mice with the parkin gene knocked out show no clinical or pathological problems.
So what can we expect to learn from models that show marked and fundamental differences to human PD? On the whole they don't reproduce the loss of DA neurons in the substantia nigra of the brain or even show any pathological changes in them; they reveal no difference in the release and re-uptake of dopamine; they lack typical Lewy Body formation; they show changes in the motor neurons of the spinal cord not seen in human PD; they suggest alpha-synuclein is not essential for DA neuron function. In fact, there is a good chance that they don't represent PD at all, but a different type of neurodegenerative disease altogether.
Yet again, GM animals have failed to further medical progress, just as their non-GM predecessors always have. The latter are based on monkey and rat models in which poisons are injected that affect their brains: overwhelmingly, clinical trials that have stemmed from the data produced have shown negative or, at best, 'unsatisfactory' results. A review of these strategies was compelled to state, 'The results of all these studies raise several questions about the true reliability and validity of animal data, the adequacy of the current working hypotheses, and the presently used tools to evaluate a specific effect.'
As always, a critical examination of the literature shows that we have non-animal research to thank for the great discoveries surrounding PD. Autopsies revealed the importance of the brain's substantia nigra; in vitro research indicated dopamine deficiency; epidemiology is uncovering the genetic basis of the disease and susceptibility to it; clinical studies and serendipity were the foundation of others.
Diabetes (Type I, or Insulin Dependent')
Type I diabetes occurs when part of the pancreas is destroyed by the body's own immune system, meaning that it cannot produce insulin. Without insulin entering the bloodstream from the pancreas, the glucose in our blood derived from the food we eat cannot be delivered to the cells of our bodies that need it for energy. Instead of getting into our cells, this glucose builds up in the blood, with extremely dangerous consequences.
Diabetes research followed the course of all other areas of medical research by turning towards animal models. In this instance, modern transgenic technologies have not been entirely responsible for this: simple breeding of rodents gave rise to the 'Non Obese Diabetic' (NOD) mouse and the BioBreeding (BB) rat, although transgenesis has been employed in an attempt to determine the role of the immune system.
Unfortunately for people suffering from diabetes all over the world, animal models have succeeded only in impeding and misleading researchers. Some quotes from a recent comprehensive review on the subject are extremely candid:
"Animal models... have led to misconceptions and erroneous extrapolations, as well as false expectations with regard to the efficacy of immunotherapy We argue that animal models have limited value when it comes to teaching us about Type I diabetes in humans."
"The Type I diabetes research has developed a 'selective blindness' as evidenced by its failure to recognise a number of shortcomings associated with animal models of the disease."
"Studies of transgenic animals or gene knock-out mice represent case reports that could suffer from cell biological and immunological artefacts unrelated to and incompatible with Type I diabetes in humans, or even in rats and mice."
"Animal models have, over time, proved to be more often inaccurate than accurate, especially with regard to therapeutic interventions."
Some of these reported successful therapeutic interventions in NOD mice include bee venom, castration, 'emotionality' and nicotine. Conflictingly, other examples are cold exposure and elevated temperature, and solitary housing and overcrowding. Almost 200 interventions have been shown to prevent or delay Type I diabetes in NOD mice... with no success in humans.
There are profound differences between the immune systems of mice and humans, amounting to more than 80 examples, a fact that surely invalidates any attempt to infer useful information from mouse models. Even so, the differences are generally ignored, despite them being the reason why the results from transgenic mouse studies into Type I diabetes have been difficult to understand.[97-98] In fact, NOD mice lack many immune system components present in humans that render them resistant to diabetic ketoacidosis - the most serious manifestation of diabetes, leading to coma and often death.
Type I diabetes is a complex, multifactorial disease in which there is no straightforward relationship between particular genes and the condition itself. If valuable and promising findings from human-oriented investigations had been built upon without recourse to animal models, we would undoubtedly be better poised in our search for a cure. Contrary to popular belief, animal experiments were not necessary for the discovery of insulin or its production to help diabetics; this much can be easily established by examining any full and objective account of the history of the disease. As ever, a more in depth study of the course of medical progress reveals that autopsies, clinical studies, in vitro work and medical serendipity were at the core of our understanding of and progress towards treating and curing diabetes. Patient studies revealed that the basis of the disease is an autoimmune attack on the insulin producing cells of the pancreas, and also resulted in the discovery of oral drugs that obviate the need for insulin injections in some patients. In vitro techniques allowed the discovery, purification and mass production of insulin, while human based studies continue to elucidate the genetics behind and the causes of the disease.
Alzheimer's Disease (AD) represents 70% of all dementias, affecting just under 1% of the population. It is characterised by progressive cognitive and memory decline, with the associated presence of distinctive hallmarks of AD in the brain, known as amyloid plaques and neurofibrillary tangles.
These plaques and tangles were discovered via autopsies of affected patients, and have been extensively characterised since then. Plaques are composed largely of a protein called A (beta-amyloid), which is 'cut' from a naturally-occurring precursor protein known as APP. Tangles are made up of another 'normal' protein known as 'tau' that is present in all ageing human brains.
Transgenic mice have been used in various ways to investigate the formation of these plaques and tangles. Mice with mutant tau genes were created in the hope that they could shed some light upon tangle formation in the human brain affected by AD, but they failed to show any AD-like symptoms or even any sign of altered neurological function. These findings suggested that tau may be a simple effect of the disease rather than a cause, though it is now generally thought that tau is highly species-specific: tau pathology in the ageing brain is unique to human beings with the exception of a few old baboons, for example. Transgenic animals expressing large amounts of APP protein, mutant APP or with APP, completely knocked out have failed to indicate the function of the protein or its role in AD: those animals accumulating A plaques display only subtle effects, and do not develop neurofibrillary tangles or suffer from significant neurodegeneration.. The same is true for other animals engineered with genetic mutations found from screens of human AD patients, such as in the 'presenilin 1' [102,103] and 'presenilin 2' genes[102-103]. In contrast, human presenilin mutations resulting in the overproduction of Ab and plaque formation are a major cause of AD, although the exact mechanisms are not known.
In summary, animal models of AD have failed to replicate the pathology of the human disease and to shed any light upon its true causes: despite a huge investment in terms of funding, human effort and sacrificed animals, we are no further forward in knowing if AD-associated plaques and tangles are a cause or an effect of the disease. Meanwhile, animal-based research continues to mislead and cause harm. A proposed AD vaccine, for example, developed using transgenic mice (which incidentally also tested 'safe' in monkeys, rabbits and guinea pigs), had to be withdrawn after it caused serious brain inflammation in clinical trials. And, of course, human based research is continuing to pay dividends: genetic screens, clinical research and in vitro studies are forging ahead, unravelling the course of the human disease, revealing new genes and drug targets.
Available space precludes a more comprehensive précis of GM animal models of other human diseases; suffice to state that a common theme runs through them all. The disastrous consequences of modelling even a 'simple' (in genetic terms) disease such as cystic fibrosis should have resulted in all signs pointing away from the road towards GM animal research, yet it continues to be pursued with more vigour than ever. And CF is not the only such example; take, for instance, two other single-gene diseases that have been 'modelled' using transgenic mice: Tay-Sachs Disease and Lesch-Nyhan Syndrome. Tay-Sachs Disease results when a faulty gene causes the accumulation of a fatty material called 'ganglioside' in nerve cells throughout the body, leading to deafness, blindness, dementia and, ultimately, paralysis. Transgenic mice mirrored Tay-Sachs in humans by accumulating gangliosides. Unlike humans, this occurred only in specific nerve cells, and crucially the mice failed to show any Tay-Sachs symptoms.[106,107] Mice carrying similar genetic mutations to those found in humans with Lesch-Nyhan Syndrome showed none of the self-harming behaviour or mental retardation seen in the latter - a difference subsequently revealed to be due to a simple biochemical disparity between the species.[108,109] If models of a one-gene disease fail so miserably, how can we expect 'stab-in-the-dark' models of immensely complex human diseases involving many unknown genes to bear fruit?
In recent years, transgenesis has been used in what can only be considered to be a last-ditch attempt to derive some form of useful information from animals used in toxicity testing. For decades, the assessment of which chemicals, drugs, food additives and so on might pose a hazard to human health has relied heavily upon administering them to mice and rats, and examining their tissues for damage. It is now universally accepted that the correlation between results from these investigations are in the region of 5-30%, a statistic that belies claims that these tests can be in any way predictive of human response.[110,111]
And so these mice have been transformed into new, improved transgenic animals that are now more susceptible to the harmful effects of various substances - and, it is hoped, be more predictive of which substances will poison and/or cause cancer in human beings. The reality is that transgenic animals are continuing to produce inconsistent results and be of no predictive value in such assessments, and that no single transgenic animal or combination of transgenic animals performs nearly well enough to be considered sufficiently reliable for regulatory use.[112,113] For example, genetically engineered mice manipulated to investigate genes involved in cancers of the nervous system in children showed that some genes and mutations clearly associated with specific human tumours produced very different effects in mice, and that one cancer-causing genetic pathway in rats did not operate in any human tumours.
As ever, non-animal techniques are showing much more promise in this field. Toxicity and carcinogenicity screens using batteries of tests involving human cells, DNA chips, in vitro methods and computer modelling are paving the way Only stubborn and dogmatic resistance to them in favour of the 'tried and tested' approach (no matter how badly this has failed) is standing in the way of their adoption.
3. Production of Organs for Human Transplant
Due to the perennial shortage of human organs available for transplant, attempts to use animal organs in a process known as 'xenotransplantation' have been made for many years. All of them have failed due to the rejection by the host's immune system of the 'foreign' transplanted organ. This also occurs in human to human transplants, though any reaction is minimised via careful tissue matching prior to transplant followed by the prescription of immunosuppressive drugs to dampen this response. When the donor organ is from a different species, however, the host immune response can become a violent 'hyperacute rejection' in which the organ can be destroyed within minutes.
In recent times, pigs have been genetically manipulated in an attempt to overcome this problem. Pigs were chosen because they possess organs that are roughly the same size as their human counterparts.Additionally, because they are used as food animals in their billions, they do not pose ethical difficulties for most people. They have been engineered so that their organs for transplant should be less prone to rejection, by either removing surface proteins that reveal them as 'alien' in a new host, or by adding a human protein that can inhibit the molecular mechanisms responsible for rejection.[115-117]
Unfortunately for the companies that have invested tens of millions of pounds in xenotransplantation in the hope of realising the speedy and massive financial gains promised by its proponents, things have not gone according to plan. Organ rejection has proved to be a more complex process than originally thought, involving many more genes and molecular pathways that must be intercepted. The scale of the problem posed by viruses carried by pigs was clearly underestimated: there are high profile examples of infectious agents crossing species barriers, such as the Ebola and Marburg viruses from monkeys, the possible evolution of HIV from a monkey virus, BSE/CJD from cows, and recent avian flu epidemics in Asia.
Perhaps more worryingly, instances of viruses crossing to humans from pigs make grim reading: the 'Nipah' virus crossed from pigs to humans and killed more than 100 people in Malaysia in 1999; the Spanish Flu that killed up to 50 million people in 1918 is thought to have been a mutant pig flu virus , and other agents have been identified that normally infect pigs but that can also infect humans.[121-122] Clearly the danger of infection here is not only limited to potential recipients of xenotransplants: everyone is at risk. One particular hazard is a type of pig virus known as 'Porcine Endogenous Retrovirus' (PERV), and experiments have shown that these viruses can and do infect human tissue. PERVS cannot be eliminated from donor pig organs, a fact that prompted a renowned virus expert to state, 'Public health officials should resist the transplant community's clamour for animal organs in light of this data.'
A substantial question mark has been placed over the suitability of pig organs for human transplant even if these rejection problems and infection risks could be surmounted, based on basic but major physiological and biochemical differences between the organs[124,125] that mean the organs simply may not function in a human environment. Another factor that has not escaped the attention of even the most ardent supporter of xenotransplantation is the cost in terms of animal welfare: not only do the animals involved (that have included sheep, tigers, pigs, cats, lions, wolves, foxes, dingoes, dogs, hares, rabbits, baboons, monkeys, goats, guinea pigs, mice and rats) suffer from the genetic modification process as detailed earlier, but they then undergo invasive surgery, the side-effects of immunosuppressive drugs, and invariably suffer the consequences of organ failure leading to death.
As ever, there are alternatives to this exercise in futility that have been demonstrably successful where they have been implemented. Simple strategies such as encouraging lifestyle changes that prevent the need for many transplants; encouraging the 75% of people who express a willingness to carry donor cards to do so; improving organ supply and debating the introduction of an 'opt-out' scheme such as that which means organ transplants occur at almost three times the rate in Spain compared with the UK. Stem cell technologies are improving too, with the promise that they could eventually result in the production of tissues and organs for 'self-transplant'; already, they have been used to repair the hearts of heart-failure patients who no longer need transplants.
4. Pharmaceutical Factories
Human proteins are used therapeutically in the treatment of a wide range of diseases, such as multiple sclerosis, hepatitis, cancer, cystic fibrosis and malaria. These proteins have been successfully produced via a number of methods for some years, including GM bacterial and yeast cultures, cultures of mammalian and plant cells, and entire GM plant crops, with each method having distinct advantages and disadvantages. Transgenic animals have been added to this list more recently, not due to necessity, but mainly because companies producing the therapeutic proteins believe that, once developed, pharmaceutical-producing GM animals can be scaled up to a huge degree and will then generate almost limitless amounts of product very cheaply.[127-129]
Cows, chickens, goats, pigs, rabbits and sheep have been genetically engineered to produce therapeutic proteins in an industry known as 'pharming' or 'biopharming.' The animals are manipulated so that they produce these products in their milk, mostly, but also in their urine, blood, or even sperm.[130,131] Large amounts of these proteins are then purified and processed into a final product. Animal welfare concerns include all that has been mentioned previously in this report regarding the production of transgenic animals, but there are some additional problems specific to pharming. In principle, transgene expression is intended to be confined to, for example, the mammary gland in those animals engineered to produce the transgene protein product in their milk. However, 'leaky' gene expression is often detected in other tissues, and the proteins are often found in the animals' blood.[122-123] This can have severe negative health consequences,  causing animals to suffer from 'pathologies and other severe systemic effects', as reported by the National Academy of Sciences in the USA.
Scientific and medical concerns surrounding these endeavours include, in common with xenotransplantation, the risk of cross-species disease transmission. This risk, of course, is real, though it may be considered minor by patients relying upon a transgenic therapeutic protein to ameliorate their suffering and/or disease. In addition, it is a statement of fact that many if not most human proteins will not be 'as they should' structurally, functionally and biochemically unless they are produced in a human milieu, i.e. in cultured human cells. Some proteins are absolutely fine being produced in bacteria, for example, but others show marked differences - ranging from ostensibly inconsequential, superficial changes, to massive and catastrophic ones. Proteins in the latter class need to be produced in 'higher' cells... so why produce them in cow's milk instead of cultured human cells? The only answer is: profit. And to produce such therapeutic proteins in transgenic animals, with all that the process entails, when this is not strictly necessary, can be regarded as ethically abhorrent and unjustifiable, especially in cases where they could be efficiently produced using plants and other means.
Although cloned animals are not all strictly, by definition, 'genetically modified' or 'transgenic,' a brief consideration is given here because the cloning process is extremely important to transgenic research.
The technique, which seeks to produce a physical replica of another individual organism, involves fusing a cell from the individual to be cloned (which may or may not be GM) with an egg cell from a donor individual that has had its nucleus (containing its DNA) removed. The egg is then free to develop, but uses the DNA from the other individual as its 'programming,' thereby resulting in a copy of that individual.
The main scientific reasons for this activity are to develop so-called 'therapeutic cloning' and 'reproductive cloning' technologies. It is hoped that therapeutic cloning could serve to produce body parts, organs and cells that are an identical match to one's own, paving the way to safer and more effective transplants and treatments for all kinds of diseases. Reproductive cloning, meanwhile, is currently being developed to allow scientists to replicate transgenic animals of interest.
It may be that exponents of cloning, like those of transgenesis and those of many other scientific disciplines who believe in the promise of their work, overstate the potential impact of it. It may be that therapeutic cloning could be the answer to the prayers of many people suffering from a variety of diseases. But that should not overshadow considerations of the amount of work involved to achieve success, or the significant caveats intimately associated with it, or the ethical concerns of the processes involved, or the fact that, what works in one species bears no relation to what will or will not work in another.
Suffice to say here that cloning is an immensely inefficient process, with poor survival rates and a high degree of associated suffering for the animals involved. Typically, only one animal reaches adulthood for every 100 manipulated eggs; a 99% failure rate. Of these 'successful' clones, almost all animals will display some form of defect or abnormality and many will die prematurely.
The intentions of some of its most vociferous advocates must also be suspect, with human cloning, agricultural animal cloning and companion animal cloning never far from the headlines. Just recently (in August of 2005) it was reported that the world's first canine clone, an Afghan hound, had been created in South Korea. The team responsible transferred 1095 embryos into 123 surrogate mothers - but just three pregnancies resulted.