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The use of genetically modified animals

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Preparation of this report v

Summary vi

1 Introduction 1

2 What is genetic modification? 3

3 Techniques for altering genetic make-up 53.1 Selective breeding 53.2 Non-GM techniques for altering genetic make-up 53.3 GM techniques for altering genetic make-up 5

4 Uses of GM animals 94.1 Medical research: genes that cause disease 94.2 Medical research: creating GM animals to understand gene function 104.3 Toxicity testing 124.4 Therapeutic proteins 124.5 Xenotransplantation 134.6 GM animals for agricultural uses 134.7 Current use of GM animals 164.8 GM insects 16

5 Safety 195.1 Regulation 195.2 Potential hazards of GM animals 19

6 Welfare 23

7 Weighing benefits against burdens 25

8 Conclusions and recommendations 27

9 References 29

Annex A Press release 35Annex B List of respondees 37Annex C Definition of ‘genetically modified’ 39Annex D Summary of statutory regulations pertaining to GM animals 41Annex E Glossary 45

The use of genetically modified animals

Contents

Copyright © The Royal Society 2001Requests to reproduce all or part of this document should be submitted to:Science Advice SectionThe Royal Society6 Carlton House TerraceLondon SW1Y 5AG

The Royal Society The use of genetically modified animals | May 2001 | v

Professor Patrick Bateson FRS (Chair) Biological Secretary and Vice-President, Royal Society

Dr Luke Alphey Department of Zoology, University of Oxford

Professor Grahame Bulfield Roslin Institute, Edinburgh

Dr Elizabeth Fisher Imperial College, London

Professor Peter Goodfellow FRS GlaxoSmithKline

Professor Barry Keverne FRS Sub-Dept of Animal Behaviour, University of Cambridge

Professor Ian McConnell Department of Veterinary Sciences, University of Cambridge

Dr Mike Owen Imperial Cancer Research Fund

Professor Martin Raff FRS Department of Biochemistry, University College London;

Dr Jim Smith FRS Wellcome CRC Institute, Cambridge

Secretariat

Dr Rebecca Bowden Science Advice Section, Royal Society

Miss Ruth Cooper Science Advice Section, Royal Society

Dr Jofey Craig Science Advice Section, Royal Society;

Ms Sarah Teather Science Advice Section, Royal Society

Preparation of this reportThis report has been endorsed by the Council of the Royal Society. It has been prepared by the Royal Society workinggroup on the use of genetically modified animals. The members of the working group were:

The Royal Society The use of genetically modified animals | May 2001 | vii

1 The Royal Society appointed a group of experts tooutline the current evidence relating to the medicaland agricultural uses of genetically modified (GM)animals. The group considered likely future areas ofresearch and current legislation governing thedevelopment and uses of GM animals in the UK. Itsreport has been endorsed by the Council of theSociety and aims to inform policy development inthis area. It will also be of interest both to researchersin the field and to the general public.

2 This report is primarily about the scientific issuesinvolved in the genetic modification of animals.While it does not address social and political issues, itdoes touch on some of the separate moral issues thatmay be involved in weighing up the burdens andbenefits of using GM animals. The debate about GManimals must take account of wider issues than thescience alone, but the Society wishes to stress theimportance of informing such debate with soundscientific evidence.

3 The various techniques for altering the geneticmake-up of an animal are explained in the report.Some, such as selective breeding or exposure tochemicals and radiation, have been used for manyyears, while others, such as the use of embryonicstem cells and genetic modification, are the result ofmore recent developments.

4 Application of genetic modification technology toanimals can be used in medical research to createmodels of human disease. Such models help identifydisease pathways and allow assessment of newtherapies. Analysing gene function is an area inwhich the use of GM animals is likely to risesignificantly, because by modifying a gene, itsvarious roles in different functional systems of thebody can be identified.

5 GM animals producing in their milk or other tissuessubstances of benefit to humans have beendeveloped for a number of reasons. (a) Manyproteins, such as blood-clotting factors andantibodies, can be formed only in the cells ofcomplex animals. (b) The proteins, such as humanalbumin, are required on a scale that would not befeasible with other methods such as mammalian cellculture. (c) Extracting material from human tissues isfraught with danger because of possiblecontamination with viruses.

6 In agriculture GM animals are being developedprimarily to produce disease-resistant animals,produce desirable alterations to growth rates or feedconversion efficiency, make leaner meat, and

enhance anti-microbial properties of milk fornewborn animals. Much of the technology is at anearly stage and the Society believes that furtherresearch will be needed before developments aimedat growth modification have commercial application.There is also need for a detailed analysis of thegenetic control of normal muscle growth,development and physiology in animals, both in GManimals and also in animals bred via selectivebreeding techniques, so that any genetically alteredtrait is consistent with good welfare.

7 Since the development of disease-resistant animalsmay have the potential to prevent disease in farmanimals, the Society recommends that researchefforts on this technology particularly address therequirements of less developed countries.Cooperation between the public and private sectorsis needed and will involve a willingness to shareknowledge, currently restricted under patent andlicensing agreements.

8 GM insects that carry human disease can be createdso that they are incapable of transmitting thedisease. Replacement of the wild population withsuch strains could reduce or eliminate diseasetransmission. Numbers can also be reduced bygenetic modifications that interfere withreproduction. GM insects also have a role in studyingthe processes involved in the development of a fully-formed adult from a fertilised egg. This is becauseinsects share a great many genes in common withmammals, including humans, and the underlyingmechanisms of development are similar.

9 In its recent report on biotechnology and food, theRoyal Society of Canada concluded that if GM fishescaped, the consequences for wild stocks and theenvironment would be uncertain. The effectivenessof attempting to render GM fish sterile is alsouncertain. Therefore, the report recommended amoratorium on the rearing of GM fish in marine pensand suggested that approval for commercialproduction should be conditional on the rearing ofGM fish in land-locked facilities. The Royal Society ofLondon endorses these recommendations.

10 All GM animals developed in the UK, whatever theirintended use, must be assessed by a comprehensiveframework of committees and legislation thatregulate and provide advice on GM animals. Policy inthis area is overseen by the new Agriculture andEnvironment Biotechnology Commission (AEBC),which is independent of government. The RoyalSociety welcomes the setting-up of a sub-group ofthe AEBC, looking at legislative concerns pertaining

Summary

The Royal Societyviii | May 2001 | The use of genetically modified animals

to GM animals. The Cabinet BiotechnologyCommittee is responsible for coordinatinggovernment policy on legislation in this area. Giventhe complexity of the regulations, the Societyrecommends that an authoritative, easy-to-understand handbook be produced by one of therelevant government departments explaining tolaboratory scientists and other interested partiesexactly what controls are in place, whichorganisations are involved, and what the procedureis for obtaining permission to undertake research.

11 Possible hazards of developing GM animals includenew or increased allergic reactions in humans to theanimals (if used as a food source); possible toxiceffects (from the production of toxins or otherbiologically active proteins) on the environment;adverse effects on other animals from a change inbehaviour such as increased aggression; changes inthe ability of the animal to act as a human diseasereservoir; and the effect on the ecosystem if theanimal is released into the environment. Thelikelihood of these things happening and theirpotential impacts are discussed in this report.

12 The potential benefits of genetic modification inanimals may be great, but so too may be the potentialcosts. Those responding to our press release identifiedwelfare costs as the greatest issue of concern. Theseissues are summarised in this report and are thesubject of other studies underway at present.

13 The Royal Society believes that some concerns aboutanimal welfare and food safety aspects of foodanimal biotechnology are justified. This reportconcludes that more information should be soughton the presence and extent of any adverse welfareeffects of producing and using GM animals. Also, thesuitability of currently available methods of assessingthe welfare of laboratory animals for all categories ofGM animals should be investigated. Detailedanalyses of the genetic control of normal musclegrowth, development and physiology in animals are

recommended so that any genetically altered trait isconsistent with good welfare. The Society believes,however, that investigating methods of assessingwelfare and ensuring that any genetically alteredtrait is consistent with good welfare applies equallyto animals bred by the conventional technique ofselection and that genetic modification technologydoes not raise major new issues in this area. Theappropriate moral stance is to minimise animalsuffering and maximise the benefits to medicine,agriculture and fundamental understanding.

14 Although genetic modification is capable ofgenerating special welfare problems, in the Society’sview, no qualitative distinction in terms of welfarecan be made between genetic modification usingmodern genetic modification technology andmodification produced by artificial selection,chemicals or radiation. Indeed, the targetedcharacter of modern genetic technology mayprovide fewer welfare problems than the oldertechniques and it may identify areas of concern morerapidly.

15 In conclusion, the development of GM animals hasbeen hugely beneficial in many areas, not least intoresearch on the causes and possible treatments ofdisease. It also has the potential to bring about otherbenefits, but serious concerns remain about welfareand health and safety issues that need to beaddressed if these benefits are to be realised.Continued research on the welfare and uses of GManimals, funded in part from public sources, andwith the results made openly available, is essential ifthese uncertainties are to be properly addressed andthe risks understood.

16 Those involved in the technology, whether in thedevelopment of legislation or in the application ofthe scientific developments, should engage in anopen and frank debate with the public, andrecognise and address the concerns of the publicabout these issues.

1 This report is primarily about the scientific issuesinvolved in the genetic modification of animals. Priorto its preparation a press release was issued (AnnexA); the organisations that responded are listed inAnnex B. The Royal Society asked for evidencerelating to the costs and benefits of geneticallymodifying animals. In addition to the general call forevidence contained within the press release, anumber of discussions were held with those involvedin implementing the legislation to ensure that anyconcerns in that area were specifically addressed.The Society stated from the outset that it wouldconcentrate on the state of current scientificknowledge and practice in this area because that isits expertise. Therefore, this report does not addresssocial and political issues. However, this report doesaddress some of the separate moral issues that maybe involved in weighing up the burdens and benefitsof using GM animals. Such moral concerns formed amajor proportion of submissions to the study by

interested organisations. Other groups such as theHome Office’s Animal Procedures Committee (APC)and the Joint Working Group on Refinement (BritishVeterinary Association Animal Welfare Foundation/Fund for the Replacement of Animals in MedicalExperiments / Royal Society for the Prevention ofCruelty to Animals/Universities Federation for AnimalWelfare; BVAAWF/FRAME/RSPCA/UFAW) will beaddressing these matters in detail in separatereports. This report examines genetic modification ofvertebrates such as mammals, birds, fish andamphibians, as well as invertebrates such as insects.Only these groups of animals that have beengenetically modified will be considered here.Xenotransplantation is not included in detail as it isthe subject of separate work by the Society. Thepublic debate about GM animals must take accountof wider issues than the science alone, but theSociety wishes to stress the importance of informingdebate with sound scientific evidence.

The Royal Society The use of genetically modified animals | May 2001 | 1

1 Introduction

2 The characteristics of an animal are stronglyinfluenced by its DNA (deoxyribonucleic acid). DNAprovides inherited information influencing how theorganism will be constructed. Genes areindependently inherited units that provide the codefor the proteins from which bodies and behaviourdevelop. The overall characteristics of an animal willdepend, among other things, on which genes it hasreceived from its parents, and whether or not thosegenes are ‘switched on’ (expressed). Most genes arecontained within the nucleus of the cell, but someare found in other cellular structures known asmitochondria. The overall genetic make-up of theindividual is known as its genotype.

3 Genes in the cell nucleus are arranged along anumber of chromosomes. In most vertebrates, thechromosomes are paired, so that a gene on onechromosome is matched with a gene on the pairedchromosome, with the exception of males, whichhave two unpaired sex chromosomes (X and Y).These genes may be identical, in which case theindividual is referred to as homozygous for thatgene, or they may differ, in which case theindividual is referred to as heterozygous for thatgene pair.

4 The products of genes (proteins) interact with eachother and with other chemicals found in the cell.Furthermore, interactions between the developingindividual and the environment in which it is growingup will have decisive effects on the individual’s adult

characteristics. The overall physical characteristics ofthe individual are known collectively as its phenotype.

5 Scientists have used a number of techniques in order toproduce genetic changes in animals. These include themutation of genes with radiation, chemicals andviruses, and are outlined below. The legal definition of a‘genetically modified organism’ (GMO) applies to anorganism whose genetic material has been altered in away that does not occur naturally by mating and/ornatural recombination of its genes (see Annex C). Itshould be noted that, even though this definition seeksto draw a sharp distinction between artificial andnatural processes, mutation of specific genes occursspontaneously under natural conditions.

6 For the purposes of this report, the term ‘GM animal’ ismore restricted than the legal definition – it refers toanimals modified either via a technique known astransgenesis (when individual genes from the same ora different species are inserted into another individual)or by the targeting of specific changes in individualgenes or chromosomes within a single species –targeted removal of genes (knock-outs) or targetedaddition of genes (knock-ins). New technologies arearising constantly, and ‘chromosome engineering’,which creates GM animals carrying large-scale DNArearrangements, is now being used.71 Transgenesisdoes not include the techniques of radiation, chemicalor viral mutagenesis, selective breeding techniqueswhich exploit pre-existing mutation/genetic variation,nor does it include cloning.


2 What is genetic modification?

3.1 Selective breeding

7 Ever since dogs, and then farm animals, weredomesticated, humans have been selectivelybreeding them for their useful, commerciallyimportant or ‘fancy’ characteristics. This sort ofbreeding relies on the natural genetic variationalready available in populations, based on naturallyoccurring spontaneous mutations caused bymistakes in the copying of the genetic materialduring cell divisions, as well as those caused bynatural radiation, internal oxidative damage etc,which happen about once in every 10–100,000individuals, and has increased in efficiency with theapplication of quantitative genetic techniques in thelast 50 years. The biggest impact on farm animals hasbeen on pigs and poultry, and with companionanimals, resulting, for example, in all the breeds andvarieties of dogs. Commercial broiler chickens havebeen selected for over 50 generations for growthrate and now grow at four to five times the rate ofthe original breeds, making chicken the commonestand cheapest of meats compared with the expensiveluxury it was in the 1940s. Similarly, the modern dairycow differs significantly from its ancestor, as does themodern large white pig from wild boar.

8 Selective breeding brings with it problems: as mostcharacteristics selected are controlled by manygenes, whose number and action are unknown,after many generations of selection deleterioussecondary effects can appear. With chickens thisincludes increases in fat, poor fertility and legabnormalities, which have caused breeders to makechanges in the selection protocols. With dogs,selection, together with inbreeding, has caused theappearance of serious genetic disease in severalbreeds. About 300 genetic recessive conditions thatcan result in serious clinical diseases in offspring arecarried by apparently healthy dogs.

9 Selective breeding contrasts with geneticmodification technology in that many genes ofunknown action are changed, whereas with geneticmodification both the gene and often its primaryfunction are known, giving at least some indicationof its effects on physiology and development.

3.2 Non-genetic modification techniques foraltering genetic make-up

10 Three common mutagenic techniques may be usedto produce random genetic changes: exposure toradiation, chemicals or viruses. When such anexposed animal breeds, the offspring tend to have

random genetic changes and chromosomalrearrangements that may give rise to new phenotypes,some of which may mimic human diseases. Forexample, offspring of animals exposed to high doses ofX-rays have been used to study cancers.31,103 The use ofX-rays as a mutagen is based on the studies of Mulleron irradiated Drosophila (a fruit-fly widely used ingenetic research)56 and has been used for fundamentalgenetic research in insects and other invertebrates.Exposure to chemical mutagens has produced mousemodels of human disorders such as phenylketonuria,X-linked muscular dystrophy, and polycystic kidneydisease,39,57, and exposure to viruses has been used toidentify novel cancer-causing genes and to disruptgenes in embryonic stem(ES) cells as a way ofgenerating mutant mice.4,87,115

Cloning11 A clone is an organism, cell or microbe derived from

a single ancestor by asexual means. Hence cloninginvolves no genetic modification, although it is oftengrouped with it as it is regarded as another exampleof biological engineering.

12 Cloning can be achieved by splitting the cells of anembryo (to create identical twins) or by a techniqueknown as cell nuclear transfer (CNT). In CNT, thenucleus from a cell of an animal, for example fromthe skin, is removed in culture and transplanted intoan egg cell, which has had its nucleus removed. If thisegg cell is given an electric pulse it may begin todivide and to form an embryo, which can then beimplanted into the uterus of a foster mother. Thistechnique was used to create Dolly the sheep.110

13 Although the technique itself does not involvegenetic engineering, it can be used in conjunctionwith genetic modification technology (see below) toproduce GM animals. The animal cell is geneticallymodified by transgenesis (see below) and then theCNT technique described above is used, transferringthe nucleus of the modified cell to an egg cell thathas had its nucleus removed. The overall process iscurrently rather inefficient.44

14 The Society issued two reports in 2000 examining theissues surrounding human therapeutic cloning.78,7

3.3 Genetic modification techniques foraltering genetic make-up

Transgenesis15 In the 1980s the technique known as transgenesis

revolutionised the ability to manipulate anorganism’s genome. For the first time scientists were


3 Techniques for altering genetic make-up

able to add genes and make changes in specificgenes in the living organism, with a view tomodelling human disease or to testing if certainmutations cause a disease. The technique is alsoused to analyse the normal role of particular genes inthe living organism. These so-called transgenic, orgenetically modified(GM), animals contain foreignDNA, often extra copies of a gene from anotherspecies, which may be human.

16 The most common route for producing a GM animalis to inject foreign DNA into a fertilised egg, alsoknown as ‘microinjection’. For mammals, injectedeggs are placed into a ‘foster’ mother where theydevelop to term and offspring are born normally,carrying the extra, foreign DNA. This DNA is nowpart of a chromosome, so when the GM animalmates and produces offspring, the transgene isinherited in the same way as any other DNA and aline of GM animals is bred that carries the extra DNA.The first GM animal, a mouse, was made in the early1980s,29 and this technology has been successfullyapplied to most mammals, including cattle, pigs andsheep,33,89 poultry,51 fish,36 and also Drosophila82 andother insects.

DNA targeting and inducible mutations17 The transgenesis described above allows the

addition of extra genes to the animal genome. In thisway certain human diseases can be modelled, inparticular ‘dominant’ diseases that are caused byhaving one copy of an aberrant gene. However,many human genetic diseases are caused byrelatively subtle changes in specific genes, eachvariant being known as an ‘allele’ of that gene. Forexample, in ‘recessive disorders’ if the gene in onlyone of two paired chromosomes is impaired theindividual is said to be heterozygous for that gene(hetero = mixed). These recessive alleles only exert adamaging effect when paired with another impairedallele – in other words when the individual ishomozygous for faulty alleles of the gene. Someonewith an impaired and an unimpaired gene is a carrierand shows no sign of the disease, but someone withtwo copies of the impaired form of the gene willdevelop the disease. Therefore, to model recessivediseases, researchers need to create specific changesin both copies of a gene of interest. This feat becamepossible in the late 1980s by the development of EScell technology,8,27 in combination withdevelopments in molecular biology.97

18 The equivalent technique for insects has onlyrecently been developed and has so far beendemonstrated only for a single species: Drosophilamelanogaster.75 However, the much greater ease ofgenerating and screening random mutations bymeans other than genetic modification in Drosophilahas meant that researchers have been able to

generate large collections of random mutants andscreen them for mutants in the gene or genes ofinterest. These screens may depend on chemicalmutagenesis, which does not necessarily involve theuse of GM animals, although engineered geneticelements are now commonly used as mutagens.Large-scale screens aimed at generating mutants inthe majority of the genes of Drosophila have beenundertaken by this method as it greatly facilitates theidentification of the mutant gene.93

Genetic modification of embryonic stem (ES) cells19 ES cells are taken from very early embryos and retain

the ability to form most, if not all, of the specialisedcell types of the adult. ES cells can also be grownindefinitely in tissue culture. The use of ES cells wasdeveloped in mice in the 1990s to overcome thelimitations of producing GM animals bymicroinjection.8,97 To date it has only been possible tomake ES cells from a few strains of mice. Manyattempts were made, over a period of a decade, todevelop ES cells in rats and farm animals but withoutsuccess. In farm animals it was because of this failurethat attempts were made to reprogrammedifferentiated cells so that they regained theirtotipotency; it was this approach that led to thecloning of the sheep Megan and Morag frompartially differentiated embryo cells and then Dollyfrom differentiated mammary gland cells. Recently,human ES-like cells have been produced in the USA85

and work is ongoing in rats, primates and farmanimals but with limited success.

20 To make a mutation in a gene of interest – ‘genetargeting’ – scientists use a combination ofmolecular biological and tissue culture techniques toalter one of the two copies of the gene in ES cells tocreate a modified cell. The modified ES cell line isgrown in culture, and then the cells are injected intoa very early embryo so that it will contain a mixture ofboth unmodified cells and modified cells (chimaera).This embryo is re-implanted into a foster mother.During development, the modified ES cells maydifferentiate into sperm or egg cells and, if so, theDNA change could be passed onto the nextgeneration of animals when the animal is bred. Thusa new strain of animals that carry a specific, targeted,change in their DNA, can be bred. The first targetedgene mutation in mouse ES cells was described in1987.97

21 Many gene-targeting experiments are designed tostop production of a protein by a particular gene – sothe gene function is ‘knocked-out’ and a strain of‘knock-out’ animals is produced. However, in someexperiments, it is important to put a piece of DNAinto a specific gene to modify the type of proteinproduced or the way it is regulated. This is doneusing the same ES cell technology, and a ‘knock-in’

The Royal Society6 | May 2001 | The use of genetically modified animals

animal is created. In other experiments precisechanges can be made to alter slightly the nature of aprotein, perhaps mimicking a human disorder. It isalso possible to model human diseases such as thoseoccurring later in life, or in certain tissues, byinducing mutations in specific genes at particulartimes or in particular tissues. Other types of modelcan be made that delete or add in large regions of achromosome containing many genes, so modelling

the human ‘chromosomal’ syndromes such asDown’s syndrome.71,90

22 Finally, the relative inefficiency of the techniquesinvolved in producing GM mammals has raisedconcerns, in particular with respect to any welfareimplications to the animals caused by any discomfortinvolved in obtaining eggs from the animals and inthe high death rates of fetuses during development.


4.1 Medical research: genes that cause disease

23 Application of genetic modification technology toanimals can be used in medical research to createmodels of human disease. Such models helpelucidate disease pathways and allow assessment ofnew therapies.

Creating models of human disease to understanddisease processes24 To understand disease processes, researchers need

access to affected tissues and cells at all stages of thedisease. Tissue culture systems in which cells aregrown in incubators have been extremely importantin understanding disease processes, but the methodsfor growing cells from many tissues remain to bedeveloped. Indeed, while non-dividing cells such asneurons can be grown in culture, they fail to makethe complexity of cell types and structures thatrepresent brain regions. In this sense they fail tosubstitute for whole organs or model processeswhere the development involves interactionbetween many cell types that represent a functionalstructure. Animal models, whether GM or non-GM,give us access to these tissue types. Equallyimportantly, human diseases often involve complexinteractions between different tissues at differentstages of life. Animal models allow researchers tolook at the whole organism and so assess interactionbetween many organs and systems, for example theimmune system and the pancreas in diabetes, orbehaviour and the brain in models of depression, orthe effects of diet on embryo development duringpregnancy.

25 The deliberate production of disease modelsinevitably has harmful effects. Although there maybe a welfare benefit from using GM animals,because they may be a better model of humandisease and so require fewer animals to gainconclusive results, the generation of animals withdiseases raises moral concerns for many people.These issues are discussed in more detail in section 6.In general, the welfare implications of any diseasemodel must be evaluated on an individual basis, assome disease models may have little or no ill effecton the animal whereas others may cause moredisability. The cost–benefit assessment of suchmodels in the UK must be assessed in accordancewith the Animal (Scientific Procedures) Act 1986,and is dealt with in more detail in Annex D.

26 For most human genetic diseases, naturallyoccurring animal models are rare, probably becausesuch animals quickly die in the wild. Thus when ananimal with a particular disease is needed for

research, scientists can attempt to make a model,usually in the mouse. Diseases arising from singlegene mutations, such as sickle cell anaemia30 orthallasaemia17,61,113 can be modelled in mice becausehumans and mice share most genes, having evolvedfrom a common ancestor. Genetic modificationtechnologies can be used to make mice with amutation in any gene. Current technology alsoallows researchers to make genetic changes atspecific times, or in specific tissues. In addition, large-scale changes that model chromosomal disorderscan also be made.71 Other types of model arepossible so that mice become susceptible to humantransmissible diseases, such as HIV or CJD.47,86 Formany models, the mouse phenotype closelyresembles the human disease phenotype, and thesemice are valuable resources for understanding howand why the disease develops, and what can be doneto halt or reverse this process.

27 While most mammals may share similar biochemicalpathways, it is clear that many physiologicalprocesses are different. Thus it is unlikely and indeedunrealistic to expect every animal model to capturecompletely all aspects of a human disease. Anexample of this lies in common human diseases, suchas hypertension or schizophrenia, which are‘polygenic’, ie, they are the result of many genesinteracting, and most likely caused by a combinationof the environment in which a person resides and aparticular set of genes they have inherited from theirparents. For such disorders, different animal models– not necessarily GM animals – are often studieddepending on the phase of the disease beingresearched. A brief example is in the field of asthmaresearch. Asthma is a complex human polygenicdisease for which three animal models are used: theguinea-pig, the mouse or the rat, depending onwhat aspect of the disease is being studied. Variousmouse models are used to study two importantchemicals produced by the body in asthma, calledcytokines and chemokines, because more reagentsare available for measurements of these molecules inmice than in guinea-pigs or rats.5,108

28 Another example lies in research into the mostcommon genetic defect in Northern Europeans,cystic fibrosis. Four GM mice strains exist, each withdifferent mutations in the cystic fibrosis gene, andeach mouse strain models a different aspect of thedisease.21,26,72,91

29 Animal models are created, based on knowledge ofgene mutations and disease in humans, which turnout to differ phenotypically from the human diseasestate. These cases can highlight unknown


4 Uses of GM animals

biochemical pathways in both humans and mice,which is helpful for understanding disease processesand treatments. In Tay–Sachs disease, a devastatingwasting disease common in the Jewish population,the GM mouse model accumulates only limitedamounts of the neural material, known asganglioside, which is so damaging in humans.40,111

This turns out to be because a different biochemicalpathway is important in the mouse, and on furtherstudy, it was found that humans also have the samepathway, although it is much less important in usthan in mice. This previously unsuspected pathway isnow being considered for drug intervention inTay–Sachs patients.

30 While these unexpected effects are very helpful, it isimportant to try to predict the likely welfareconsequences of altering a gene, as required by thecost–benefit calculation required by the Animal(Scientific Procedures) Act 1986, which addressesthe issue of likely pain and suffering in the animal.Information on the protein expressed and the level ofexpression, the tissue in which it is expressed and themethod of excretion (ie, whether it is recovered inmilk or via urine), allows a prediction to be made ofthe possible adverse effects on the animal. On thelittle evidence presently available, it is not possible toconclude what proportion of GM lines displaysunintended and unexpected harmful effects.Nevertheless, unexpected findings from modifying aparticular gene in an animal for the first time may bequite frequent.60

31 Genetic background is important in humans for howdiseases manifest. It is also important in humans’response to drugs. Therefore, the search is on to findthe genes that ‘modify’ major disease genes,because these genes will help us understand diseaseprocesses, and individual sensitivities to treatments,and may provide useful targets for new therapeutics.Finding these ‘modifier’ genes is an exercise instatistics, which entails working with tens ofthousands of human samples at vast expense, soonly common diseases can be justified for study. Inaddition, many ethical issues arising from suchprojects remain somewhat cloudy; for example, whohas access to the genetic information on individualswho take part.

32 The same process of finding important ‘modifier’genes in the genetic background is faster andrequires fewer samples in mice, in which the samegenes as in humans, or genes affecting the samebiochemical pathways, can be identified. Thus, inmice, modifying genes may be detected by breedinga mutation – created by genetic modification orotherwise – into different mouse geneticbackgrounds, which cause the phenotype tomanifest slightly differently. By breeding mice with

different genetic backgrounds it is possible to studywhich genes are inherited with which aspects of thephenotype, and so map those genes that modify it.An early example of this came from a GM mouse thatmodels aspects of cystic fibrosis, in which a geneticmodifier was detected.81

Creating models of human disease for testing newtherapeutics33 All new drugs have to go through many years of

testing before they can be brought onto the market.Such testing studies whether a drug has any efficacyin treating a disorder, and how safe it is. The efficacycan best be studied in the closest possible model tothe human disorder and this may well mean a GManimal, usually mouse, which has been produced tomimic the human condition. Giving a drug to anormal mouse may not show any effect, whereasgiving it to a mutant mouse may give positive benefitif the drug works.

34 In comparing all the possible new drugs that arediscovered in the laboratory the vast majority arerejected before they are even tested on animalsbecause they would not be likely to treat diseasessuccessfully and safely. The drugs that are notrejected initially are then given to animals being usedas models to see if they can treat the disease beingstudied. Again only a very few of these drugs arethen further tested in animals to see if it is safe tostart testing in people. Both traditional and GManimal models are used in these processes, to ensurethat only drugs that are likely to be both safe andeffective progress to testing in human volunteers.

35 One of many recent examples of the use of GManimals for testing drug therapies lies in research intoa devastating disease called motor neuron disease,which typically kills affected individuals in their mid-40s. A gene was identified that causes one form ofthe disease, and GM mice with mutations in thisdisease were developed to mimic the humandisorder. These mice are being tested withrevolutionary new therapies to see what can slowdown or halt the inexorable progression of nervedeath. Even if these treatments appear then to beeffective in mice, it is vital that patients are notharmed by inadvertent side-effects and that thetreatments are tested for their safety in mice or ratsand another species first. The reason for using twospecies is to enable effects to be analysed in differentanimal models.

4.2 Medical research: creating GM animals tounderstand gene function

36 The information from the Human Genome Project,and the sequencing of other genomes, has


presented us with around 30,000–40,000 genes thatmake us human, and about which very little isknown. In other words, once the DNA sequence of agene has been obtained, the next step is to find outwhat it does. Analysing gene function is an area inwhich the use of GM animals, particularly GM mice,is likely to rise significantly. This is because bymodifying a gene, for example, knocking it out,scientists can learn which biological systems areaffected, and thus they can pinpoint what the genedoes. Whilst a large number of gene knock-outshave no obvious effect, some can produce modifiedphenotypes that help researchers to understand thefunction of the removed gene.

37 A GM animal with a change in a gene of unknown oronly suspected function is an exploratory model.Such models have made an enormous contributionto the understanding of many basic cellularprocesses. For example, in cancer research, morethan 60 so-called ‘oncogenes’ or cancer-causinggenes and 20 tumour suppressor genes have beendescribed, and the function of most of them hasbeen determined by the use of GM mice that eitheroverproduce the protein, or in which the genefunction has been knocked-out. Such models,because they are exploratory by definition, haveprovided many surprises that indicate their value andshow that understanding of the control of cellmultiplication and death is still far from perfect. Forexample, it is surprising that the p53 knock-outmouse – created because of the role of the proteinp53 in resistance of cancer to chemotherapy – cansurvive, because protein p53 is very important indevelopment. In view of the number of theseregulatory molecules and the interactions betweenthem it is difficult to think of any other ways in whichtheir function could be studied so effectively.Eventually it is hoped that cures for cancer will comefrom an understanding of the disease.

38 Even when gene function is thought to beunderstood, genetic modification can still producesurprises. For example, studies using knock-out micehave established a role for orexin, a peptide found inthe brain, in sleep regulation. Behavioural studieswith these mice revealed that their phenotype wasstrikingly similar to human narcolepsy patients.Narcolepsy is a disease that causes paralysing attacksof drowsiness and sleep. Moreover, dog breeds thatare susceptible to narcolepsy do not have the geneneeded to construct a receptor for orexin. Thesefindings led to the discovery that an anti-narcolepticactivates neurons that contain orexin.15,48,49

Developmental biology39 Genetic modification of several species is proving

particularly useful in enhancing the basicunderstanding of developmental biology, the study

of how a single fertilised egg develops into a fully-formed adult. Drosophila (fruit-fly), Brachydaniorerio (zebrafish) and the frog Xenopus, are discussedbelow; other species, such as mouse, have also beenused for developmental biology but are notdiscussed here.

40 Methods for reproducibly creating stable, heritable GMinsects were developed almost 20 years ago, using thewell-known genetic model insect Drosophilamelanogaster.82,92 It is generally considered harmless asit is neither a significant agricultural pest nor a diseasevector and no adverse consequences to human healthor the environment of this large-scale geneticengineering have been reported. Many thousands ofdifferent GM strains of Drosophila have subsequentlybeen produced in laboratories around the world, andthere are far more GM strains of Drosophila than thereare of all other GM insects combined. It has becomethe paramount model organism for studying animaldevelopment and genetics. One of the great surprisesof this work has been the extent of the similarity of theunderlying mechanisms and molecules ofdevelopment between flies and humans. In otherwords, though flies and humans look quite different, inmolecular and developmental terms they are muchmore similar than anyone had imagined. This isbecause insects share a great many genes in commonwith mammals, including humans. To give a singleexample, it is now clear that the insect’s compound eyeand the human eye, despite their radically differentstructure, are both specified by the same masterregulatory gene, and other aspects of theirdevelopment are much more similar than anyonewould have imagined only 10 years ago.69 The use ofGM flies to analyse gene function has been a key partof these studies for nearly 20 years, during which timethe precision and power of these genetic tools havemade their use ubiquitous. One simple example is theability to express in the fly the mammalian counterpartsof fly genes, in order to determine exactly to whatextent their functions are similar. This was done withthe mouse homologue of a gene to show that it coulddirect eye development in flies.32 Modern Drosophilaresearch is completely dependent on the use of geneticmodification for the generation and analysis ofmutants,93,94 and for the insertion and expression ofgenes either from Drosophila or from other sources.9

41 Zebrafish has become a major model system fordevelopmental studies in the last 10 years and indeedmost work on GM fish in basic research involves thezebrafish. This is primarily because it is relativelystraightforward to perform genetic analysis inzebrafish and to identify the function of novel genes.At the moment, little has been published on GMzebrafish but many groups are now using thistechnology and the use of genetic modification is likelyto increase over the next 5 years. It is possible to


generate GM zebrafish in which green fluorescentprotein (GFP) is expressed under the control of specificpromoter/enhancer DNA elements.36 The use of thistechnology enables the researcher to monitor specificpopulations of cells via fluorescent labelling. These cellscan be followed over time in living fish, allowinganalysis of the divisions, migrations, morphologies andpatterns of death of the labelled cells. This allows trulyunprecedented analysis of cell behaviour and fate in aliving vertebrate.37 Furthermore, the GFP fish can becrossed with mutant fish, allowing the study of thefates of cells in embryos carrying mutations that affectspecific gene functions.

42 The most widely used amphibian species for biologicalresearch is the South African claw-toed frog Xenopuslaevis. Xenopus has been extremely important in theunderstanding of development since research in thisfield began. The main advantage of Xenopus is thatamphibians mature externally, unlike mammals, and soare accessible at all developmental stages. Basicresearch into the development of Xenopus has beenundertaken for decades. Transgenesis has allowedresearchers to carry out the full range of geneticmodification techniques familiar to researchers on themouse, but more importantly allows the combinationof these techniques with the traditional advantages ofthe amphibian embryo. Xenopus, unlike zebrafish, hasfour limbs, so one can study limb development andlimb abnormalities, allowing study of metamorphosis.Finally, it is worth noting that in comparison withmouse, experiments with GM Xenopus embryos arequick and cheap. Again, one of the simplest, yet mostuseful, examples of the use of GM Xenopus involvesthe use of GFP. One can create GM lines of Xenopus inwhich GFP is expressed in the same pattern as aparticular gene of interest. It is then a simple matter todiscover whether treatment of a tissue with a potential‘inducing factor’ activates expression of that gene, byseeing if the cells start to glow green.

43 Recent studies making use of GM Xenopus embryosinclude the study of eye development.59 Futuredevelopments may centre on the use of a differentspecies, Xenopus tropicalis, which is smaller thanXenopus laevis, and therefore easier to keep. It has ageneration time of three to four months comparedwith approximately 18 months for X. laevis. Andfinally, and most importantly, X. tropicalis is likehumans in that it has paired chromosomes andhence two copies of each gene. It therefore contrastswith X. laevis, which appears to have undergone agenome-wide duplication.

4.3 Toxicity testing

44 The main application of GM animals to toxicitytesting at the moment is in the testing of chemicals

and drugs to ensure that they do not cause cancer,although they are also used to test for othermechanisms of toxicity as well as for damage todevelopment of the unborn child.101

45 Several rodent strains are available for testing formutagenicity by virtue of having ‘marker’ or‘reporter’ genes inserted. A ‘reporter’ gene is onethat, when altered, signals its presence underexamination. For example, in the Big Blue mousewhen a gene is mutated (under the influence of achemical) the change can be detected by introducingthe genes first into yeast cells, and cells with anymutant genes will be detected as blue.25 Clinicalobservation has not so far identified welfareproblems caused by the insertion of the markergene(s) or any additional problems, over and abovethose that might be encountered in non-GManimals, in the actual testing regime.1 In all cases, analtered gene involved in controlling cell division orcell death is inserted into the GM animals, makingthe development of cancer, the endpoint ofimportance in these tests, occur much earlier thannormal.

46 In addition to the GM animals carrying reportergenes, around five strains of mice with oncogenesare being evaluated for their ability to detectchemical carcinogens with a view to reducing thetime (6 months as opposed to 24 in traditional tests)and numbers of animals used (two or three groups of20–30 animals as opposed to four groups of 100animals) for toxicology tests.1 The work is beingcoordinated by the International Life SciencesInstitute (Washington). The GM strains have specificmutations in their oncogenes (ie, the genesresponsible for the control of cell growth) andtherefore develop cancer far more quickly than wild-type mice. These models are then sensitive todifferent types of carcinogens.16,34,35,95,96,114

47 Mice have also been modified to act as assays to testfor specific effects that previously could only betested on higher (more complex) primates.12

4.4 Therapeutic proteins

48 GM animals producing human therapeutics in theirmilk or other tissues have been developed for anumber of reasons: (1) many proteins requirecomplex modification that can only occur correctly inthe cell of a more complex animal (eg, not inEscherichia coli, yeast or plants), for example, humanblood-clotting factor IX, antibodies; (2) the proteinsare required in large amounts that would not befeasible by other methods (eg, mammalian cellculture), for example, human albumin or α1antitrypsin (this protein was produced at the level of


30 grams per litre in the milk of Tracy, the first GMsheep);109 (3) safety when compared with extractingmaterial from human tissues (eg, the AIDS virus).Where the protein is benign and is produced in milk,this approach does not have any adverse welfareconsequences for the GM animals as a result of thegenetic change.42

49 Three major companies are using genetic modificationtechnology to produce human therapeutic proteins inthe milk of sheep, goats or cattle: PPL Therapeutics Ltd(UK), Pharming BV (Netherlands) and GenzymeTransgenics (USA). Between them they have about 30proteins (including antibodies) at various stages ofdevelopment, including some in advanced clinicaltrials.

50 Insects can potentially be used for proteinproduction, in much the same way as farm animals(see above). A few insects are commercially farmedon a large scale and genetic modification methodshave the potential to introduce tailoredmodifications to the product. For example, researchis in progress to alter the properties of silk by usingGM silk moth caterpillars.

4.5 Xenotransplantation

51 One of the earliest genetic modifications of largeranimals was the development of GM pigs carrying ahuman gene that could prevent the acute rejectionof organs transplanted between pigs and humans.The transplantation of tissues from one species toanother is known as xenotransplantation. Wheneverpig tissue is transplanted into another species,antibodies in the recipient attack the transplantedorgan, and the consequent inflammatory responseleads to graft rejection. By introducing amodification to some of the proteins on cells thatcause the body to raise an immune response, calledcomplement control proteins, rejection of thetransplant can be prevented.

52 Overcoming this type of graft rejection is a majormedical breakthrough that could provide apermanent solution to the serious shortage of organsand cells for transplantation in humans. Pig heartvalves from non-GM pigs have in the past beenwidely and successfully used in heart valvereplacement in humans and the use ofxenotransplants is a more advanced medicalapplication of an established and ethically acceptedprocedure. It also has application in providing asuperior approach to the use of organ-based, life-support therapies in humans. For example, bloodfrom a patient with drug-induced damage to the livercan be passed through a GM pig’s liver outside thepatient’s body to provide a life-support system that

cleans the blood. This procedure allows time for thedamaged human liver to recover proper function.

53 However, there are a large number of clinical, safetyand regulatory issues that will have to be addressedwith xenotransplantation before it can become aclinical reality. These issues are being addressed andkept under review by the United KingdomXenotransplantation Interim Regulatory Authority(UKXIRA) (see section 5.1). This subject is not dealtwith in detail in this report as it has previously beeninvestigated by the Royal Society.76 The NuffieldCouncil on Bioethics has also issued a more detailedanalysis of this topic.58

4.6 GM animals for agricultural uses

54 The aims in farm animal transgenesis are: tointroduce genes that confer disease resistance toanimal pathogens, eg, development oftrypanosomiasis or foot and mouth disease-resistantcattle; to enhance resistance to parasitism; to makedesirable alterations to growth rates or feedconversion efficiency; and to alter meat and milkcomposition to produce either leaner meat orenhanced anti-microbial properties of milk fornewborn animals. Much of the technology is at anearly stage and it is likely to be at least a decadebefore large animals with modified or deleted genesof commercial value will have been evaluated andapproved by the various regulatory bodies.

55 Initial research on altering growth hormone geneexpression in pigs gave rise to unacceptable growthabnormalities since the action of the growthhormone gene was not properly understood orcontrolled.65 At present all the approaches beingdeveloped are experimental.68 However, geneticselection in the breeding of farm animals fordesirable traits is an inherent aspect of modernagriculture and transgenesis is an accelerated versionof selective animal breeding. It is more precise inbeing aimed at directed and permanent alteration ofspecific traits that cannot be achieved byconventional breeding strategies.

Modification of growth56 The initial discovery that growth hormone levels

could be altered genetically in mice, leading toenhanced growth rates,60 triggered a series ofexperimental studies on GM farm animals. Alteringgrowth hormone levels in pigs and sheep hassometimes resulted in unacceptable pathologicaland hormonal dysfunction in early studies such asbone growth abnormalities (acromegaly), lamenessand infertility.68 However, a mechanism that allowsbetter control of expression of the gene (by alteringlevels of zinc in the diet), and hence levels of


hormone, has been developed successfully in sheepand pigs, allowing an increase in growth rateswithout any significant abnormalities.67 However,the Society believes that further research is neededbefore these developments offer any prospect ofcommercial application. Detailed analysis of thegenetic control of normal muscle growth,development and physiology in animals is needed sothat any genetically altered trait is consistent withgood welfare, both in GM animals and also inanimals bred via selective breeding techniques. TheSociety has recently recommended that the Ministryof Agriculture, Fisheries and Food (MAFF) shouldfund research into the welfare implications of GManimals for agricultural use.

57 Enhancing growth with genetic modification has beenespecially successful in fish. Gene transfer into theearly fish embryo is being performed in several speciesincluding trout, salmon, catfish, tilapia, coho salmon,chinook and carp. Genetic modification with growthhormone has led to a threefold increase in weight, andthe potential for exploiting colder waters.70

Genetically modified salmon have been shown toconsume 250% more food than size-matched non-GM salmon in a competitive situation,24 suggesting aheightened feeding motivation.

58 It can take 10 years to produce a stable line of GMsalmon. Consequently, the stability of the modifiedgenotypes is largely unknown. Before stability isachieved, the variability of GM salmon in terms of,for example, survival rate and speed of swimmingmay reflect variation in effect depending on wherethe transgene is incorporated into the fish genome,which could vary from one line to another.

59 A different approach to enhancing growth in fishthat does not involve genetically modifying theanimal has been to use plasmids that expressrainbow trout growth hormone in yeast. The yeasthas been used as an additive in food. Daily feedingwith recombinant growth hormone produced fastergrowth than in the normal fish. Such a procedure ispracticable and may be economically viable.102

Recombinant growth hormone is already used incattle in the USA, but safety concerns have resultedin the EU banning cattle imports from the USA.

60 The suggested heightened feeding motivation ofthese GM fish raises the possibility that any escapedanimals could readily compete successfully in thewild, raising concerns for their impact on theecosystem; potential environmental hazards of GManimals are discussed in section 5.2.

Modification for production61 Insulin-like growth factors are released by the liver

and are the active agents causing the growth of

bones and muscle in response to growth hormone.The effects of these factors are diverse, but it hasbeen possible to isolate part of their growth-promoting influence on muscle by using a geneconstruct that allows selective expression in thestriated muscle only in female pigs. In contrast to theGM animals with increased growth hormone, nopathological abnormalities or related healthproblems were found in these GM pigs and thewelfare of the animals was not compromised.20,66

62 Section 4.4 discussed the modification of animals toproduce therapeutically important proteins in theirmilk. Attempts have also been made to enhance thenutritional status of the milk,10,52 for example, toachieve faster growth or disease resistance in theyoung suckling animal, or to eliminate allergenicfactors in cow’s milk destined for humanconsumption. The emphasis here is on altering milkcomposition and not yield, since it is undesirableand unnecessary to use genetic modificationapproaches to increase milk yield in cows as themodern dairy cow is close to its physiological limitsin terms of milk production.

63 For example, GM pigs have been producedexpressing a bovine gene for a milk protein. Thesepigs produce a 50% increase in the protein contentof their milk, and the piglets suckled on the GM sowhave a greater gain in weight (10%) and improvedhealth.6 GM pigs have also been produced to expresshigh levels of specific antibodies to control porcinegastro-enteritis,83 and high levels of another proteincalled lysostaphin have been successfully engineeredin the mammary gland of mice and shown to protectagainst mastitis; this has considerable potential forcontrol of mastitis in cattle.

64 Other potential future developments in this areainclude altering the casein and whey composition ofmilk to improve cheese production, and increasingthe natural level of anti-microbial milk proteins.Eliminating human allergenic proteins such aslactoglobulin in cow’s milk or replacing them withless allergenic human milk proteins (‘humanising’cow’s milk) for infants, as well as reducing the fatcontent of milk, is technically possible. At present theapplications of this technology to control milkcomposition are limited to traits controlled by asingle gene, such as the synthesis of a single protein,and are unlikely to extend to alterations in lactationalphysiology, which is under the control of manygenes.

65 Current research is focused on improving woolcomposition so that it will take up dye more readilyor is less likely to shrink. This may be done by alteringthe keratin composition of wool or alteringbiochemical pathways of cysteine metabolism to


improve wool fibre strength.63,74 These are novelaspects of farm animal transgenesis, so far at a veryearly stage, although research appears to be moreadvanced in some research groups in New Zealand.

Development of disease resistance66 Conventional animal breeding for desired

production traits has in many cases resulted in animalpopulations with unique disease susceptibilities.genetic modification technology could provide ameans of producing animals resistant to many ofthese diseases, which would be of direct benefit tothose animals. Much of this research is at a very earlystage.

67 Marek’s disease, a disorder in poultry, appears to be apromising target for genetic modification technology.Marek’s disease is a herpes virus induced cancer of thelymphoid system which costs the UK poultry industry£100 million per annum and is a major welfareproblem as the disease can devastate poultry flocksand give rise to lameness, anaemia and chronicwasting in birds. Resistance to the disease appears tobe controlled by only a small number of genes,112 andtogether with the development of the chickengenome map it is hoped that it will be possible tocreate chickens resistant to this virus disease.

68 A similar strategy has been applied in attempting tocreate sheep resistant to Maedi–Visna virus, an HIV-like virus. This virus disease of sheep and goats isendemic in sheep worldwide, causing seriousproduction losses due to pneumonia, arthritis andencephalitis.18

69 Sheep and cattle resistant to prion diseases such asscrapie and bovine spongiform encephalopathy(BSE) may be produced by knocking out the PrP genein ruminants. This technique has been used in miceto create genetic resistance to transmissiblespongiform encephalopathies (TSEs).64 One of thebasic problems in trying to construct disease-resistant animals is that resistance to infectiousdisease is affected by many genes, and insertingsingle genes is unlikely to be of much value otherthan in very specific circumstances like PrP knock-outs.

70 GM animals with disease resistance could be ofpotential importance to agriculture in developingcountries. For example, trypanosomiasis is an insect-transmitted disease that has a serious impact oncattle rearing in large parts of Africa. Vaccinal,chemotherapeutic and tsetse-fly controlprogrammes have made little impact in control oftrypanosomiasis in African cattle. It is hoped that theidentification of areas on the genome in micecontrolling trypanosomiasis43 will lead to similarareas being defined in cattle, since the bovine

genome map is now better understood. If thisapproach were successful it would open the door toa genetic approach to control of cattletrypanosomiasis either based on conventionalbreeding or transgenesis. The N’Dama breed ofcattle in sub-Saharan Africa has a high geneticresistance to insect-transmitted diseases, includingtrypanosomiasis, and study of the genetics of thisresistance and transfer of the resistant genes intohigh-production status exotic dairy breeds (egFriesian cattle) for Africa could be major step forwardin overcoming the constraints on livestockproduction by insect-borne diseases in Africancattle.54 (See also section 4.8.)

71 Given that genetic modification technology may havethe potential to prevent disease in cattle in thedeveloping world, the Society recommends thatdevelopers of this technology ensure that theirefforts address the needs of less developedcountries. Cooperation between the public andprivate sectors will be needed and this will require awillingness to share knowledge, currently restrictedunder patent and licensing agreements, in order tobenefit poor farmers in the developing world.

GM animals for food use72 Despite the growing list of GM animals in

agriculture, transgenically derived animal foodproducts are still a long way off.105 No GM livestockfor food production are close to being evaluated byregulatory authorities in the UK. Difficulties arise forseveral reasons.

• The efficiency of genetic modification of the farmanimal genome is low (less than 1% of GM offspringin pigs, sheep, goats and cattle).

• Current methodologies use approaches that haveresulted in high levels of embryonic loss or damage.

• The longer breeding cycles of farm animals and lownumber of offspring (except pigs) and high financialproduction costs limit the pace at which GMlivestock can be created.

• Detailed knowledge of the farm animal genomes isstill incomplete, as are the functions of their genes.This applies in particular to understanding thegenetic factors controlling production traits; controlof normal tissue and organ-specific gene expression;control of transgene expression; the lack ofreplication of defective retroviral vectors for genetransfer and ways of improving transgeneconstructs.

• Many of the desirable traits such as diseaseresistance and production traits are polygenic andrequire the alteration and coordinated expression ofseveral genes, many of which have yet to be defined.

• Funding agencies are not supporting GM livestockprojects to a high level and returns for venture capitalare regarded as low.


• Concerns about animal welfare and food safetyaspects of food animal biotechnology are justified.

73 In summary, formidable regulatory, ethical,economic and environmental issues as well as publicconcerns will need to be addressed if commercialdevelopment of GM animals as a source of humanfood is to be progressed.

74 For GM plants, a national list of recognised non-GMand GM seeds for marketing for agricultural useexists as a quality assurance mechanism to protectfarmers. As GM animals become more common theSociety considers that an analagous list would beuseful for farmers.

4.7 Current use of GM animals

75 In 1999 the total number of procedures performedon animals (under the Animal (Scientific Procedures)Act 1986, which covers vertebrates and Octopusvulgaris) was 2,656,753 – down by 0.1% comparedwith 1998. The total number of animals used was2,569,295 (down by 1% compared with 1998). Ofthese the number of GM animals used increased by14% to 511,607. This number is likely to continue torise as the benefits from genetic modificationresearch cannot be realised unless geneticmodification research grows. However, numbers arelikely to fall again once appropriate disease modelshave been produced.

76 In 1999, 98% of GM vertebrates used were mice.Recent developments such as the production of a GMmonkey14 raise new moral and welfare issues. These arediscussed in section 6. The GM monkey (known asANDi) had a jellyfish gene inserted into it that codes forthe production of a fluorescent protein, which can beseen to fluoresce under conditions designed to visualisethat protein in the monkey. It is almost certain that thiswould not be detectable or discernible to the naked eyewhen the monkey is illuminated by blue light. However,it is known that the inserted gene can be foundthroughout the monkey’s body. Such researchdemonstrates that it is possible to genetically modifymonkeys and paves the way for more medically usefulchanges to be engineered. It should be noted that so farthe process is very inefficient. From 220 fertilised GMeggs only 126 grew into embryos, 40 of which weretransferred to surrogate mothers. Of these 40, only fivepregnancies resulted, three young were born alive, butonly one of these contained any jellyfish gene.

4.8 GM insects

77 Despite the enormous success of geneticmodification in Drosophila, genetic modification of

other insects is much more recent and limited inscale. This is primarily for technical reasons, though italso reflects the relative number of molecularbiologists working with Drosophila compared withother insects. Genetic modification of insects hasbeen attempted for several reasons, which aredescribed briefly below.

Development of genetic modification methods78 A major effort since the publication of genetic

modification methods for Drosophila in 1982 hasbeen to develop these for insects of medical oragricultural importance. This was achieved in 1995for the Mediterranean fruit-fly, an agricultural pest,50

and in 1998 for the yellow fever mosquito.19,45

Modification of other insects has rapidly followed,including an anopheline mosquito, one of thecarriers (vectors) of human malaria,13 but the totalnumber of species modified is still relatively small.Genetic modification is still a laborious andtechnically demanding exercise for most of theseinsects, so that the necessary expertise is restricted torelatively few laboratories. Work on several fronts(eg, DNA delivery, modification efficiency) is neededto make these methods more widely practicable andavailable.

Other basic science79 GM non-Drosophila insects are being and will be

used for much the same reasons as GM Drosophila –to examine fundamental biological questions such ashow brains and nervous systems work, how thedifferences between males and females arise, etc(see also section 4.2).

Refractory insects80 A major goal of research using GM insects that carry

human disease is to create strains of insects that areincapable of transmitting the disease, ie, they arerefractory to transmission. Replacement of the wildpopulation with such a refractory strain wouldreduce or eliminate disease transmission. Forexample, mosquitoes modified so as not to spreadmalaria would, if they replaced the ‘natural’ variety,spare millions of lives a year. In order to create arefractory strain, researchers are investigatingnatural insect immunity (which may also yieldantibiotic-like therapeutic agents against humandisease) and the interactions between the carrier andthe pathogen (infection) with a view to identifyingmolecules that will block transmission whenexpressed in a GM mosquito or other disease carrier.In order to be able to replace a wild population witha suitable refractory strain when one is constructed,researchers are investigating mechanisms for drivinggenes through populations. Some methods, such asmass-release, are expensive but relatively non-controversial (relative to any other environmentalrelease of a genetic modification animal), but others,


such as the use of autonomous transposons (smallsections of DNA carrying a gene and otherinformation, and capable of integrating within thegenome), raise additional issues (see section 5.2 formore information on potential hazards). Theecological impact of such large-scale releases wouldhave to be carefully reviewed prior to release.

Population control81 A major goal of research using GM insects that are

agricultural pests is to develop new strategies forcontrolling the numbers of individuals in a pestpopulation. This approach is clearly also of potentialuse against insect disease carriers. Research focuseson the addition of beneficial characteristics topredators or parasites of the pest,38 and alternativelyinto the addition of new, usually deleterious,characteristics into the pest species itself.98

Vaccine delivery82 Blood-feeding insects typically inject factors into

their host’s blood to modify clotting and behaviouraland immunological responses. If such insects couldbe engineered to inject a vaccine in the same way,then they could be used as a vaccine delivery system.The key advantage of this would be the ability of theinsects to immunise populations of wild animalsinaccessible to a conventional vaccinationprogramme. However, the concerns about thisapproach are grave since the ethical and practicalproblems appear to be insuperable, especially withrespect to human vaccines, so that such insects, evenif constructed, are unlikely ever to be released.

Environmental release83 Environmental release of GM insects, which is the

ultimate goal of several of the research programmesoutlined below, requires additional informationbeyond that required for laboratory use. Keyquestions include the stability of the transgene in thewild population, the likelihood of horizontal transferto individuals of the same or of different species andthe consequences of these events. A limited field

release of a modified natural enemy has already beenperformed.38 A limited field release of a radiation-sterilised modified pest is planned. This simplemodification, which causes expression of GFP from ajellyfish62 (see also section 4.2), would ultimatelyallow the dispersal of the released insects in a sterile-release control programme to be monitored moreaccurately.

84 A major driving force behind the development ofthese methods is the growing public concern aboutthe widespread use of chemical pesticides, coupledwith the development of insecticide resistance inmany pest strains. GM insects potentially offer aclean and extremely species-specific alternative.The sterile insect technique (SIT), an existing, non-genetic modification technology in which sterileinsects are released to compete for mating to wildfemales and so reduce their reproductive capacity,has these advantages, but is extremely costly toimplement. Nevertheless, the SIT has been usedsuccessfully to eradicate a major agricultural pest,the New World screw-worm fly, from the USA andMexico as far south as Panama and has been usedeffectively against a range of other pests. GMinsects can overcome many of the productionproblems of the SIT, leading to efficiencyimprovements on a scale that would make thisgreen technology practicable against a much widerrange of insect pests and disease vectors.84,98

85 As with GM animals for agricultural use, thesetechniques are likely to be of the greatest benefit tofarmers in the developing world. It is important thatthe research of companies and the public sector inthis area meets the needs of the developing world viaadequate funding and through cooperation andshared knowledge.

Protein production and farming86 It is likely that insects will be used to an increasing

extent in the fundamental work that has hithertobeen carried out on mammals (see also section 4.2).


5.1 Regulation

87 The framework of committees and legislation thatregulate and provide advice on GM animals iscomprehensive. These are outlined briefly here, withfurther details provided in Annex D.

88 The Advisory Committee on Genetic Modification(ACGM) is based in the Health and Safety Executive(HSE) and regulates, licenses and monitors all GMexperiments (from bacteria to sheep) from thehuman safety point of view. So first a GM animalexperiment would need their permission (these areEurope-wide regulations – Genetically ModifiedMicro-organisms (Contained Use) Directive(90/219/EEC) (revised 1998, supplemented byDirective 2001/18/EC in 2001); see Annex D for moreinformation).

89 The Home Office (HO) also licenses, regulates andmonitors experiments on vertebrates (and Octopusvulgaris) under the Animals (Scientific Procedures)Act 1986, including GM vertebrates. Scientists needboth a Personal and a Project Licence for this work tobe approved and monitored by the HO Inspectors.The HO will not release a genetic modification animal(or a line of animals) from the Act until the line hasundergone two generations of breeding tohomozygosity to the satisfaction of the HO Inspectorthat it is healthy (no GM animal has yet been releasedfrom the Act).

90 The EC Directive on the deliberate release into theenvironment of genetically modified organisms orGMOs (90/220/EEC) secures protection of humanhealth and the environment from the deliberaterelease into the environment of GMOs. If a scientistwishes to release an animal from ACGM containedpremises the proposal goes to the AdvisoryCommittee on Release into the Environment (ACRE)(a Department of the Environment, Transport andthe Regions (DETR) Committee). No animal has yetbeen released in this way.

91 The deliberate use and environmental aspects ofcontained use regulations are devolved, so whereasthe DETR has responsibility for their enforcement inEngland, decisions are taken by the ScottishExecutive, National Assembly for Wales andNorthern Ireland Assembly for enforcement inScotland, Wales and Northern Ireland respectively.The same advisory committees (ACRE and ACGM)are used in each country.

92 If at some point in the future a scientist or companywishes to market a GM animal for food, they must

apply to the Advisory Committee on Novel Foodsand Processes (ACNFP, which reports to the FoodStandards Agency (FSA)). It is not envisaged that thisis likely to happen in the next few years at least.

93 Xenotransplantation is regulated both by the UKXenotransplantation Interim Regulatory Authority(UKXIRA) and the Home Office Animal ProceduresCommittee. There is some joint membership andliaison.

94 Finally, policy in this area is overseen by the newAgriculture and Environment BiotechnologyCommission (AEBC). The Royal Society welcomes thesetting-up of a sub-group of the AEBC to look atlegislative concerns in animal biotechnology as thisarea is complex and needs to be examined to ensureno conflicts or gaps occur in the legislation. TheCabinet Biotechnology Committee has responsibilityat ministerial level for coordinating governmentpolicy on legislation in this area.

95 A number of technical guidance notes have beenpublished on the different parts of the legislation.These are available on the DETR’s website(http://www.detr.gov.uk/). Both legislation and thevarious committees are complex because some arestatutory and some are advisory. The generalstrategic overarching commissions that wereinitiated with the purpose of identifying gaps are theHuman Genetics Commission, the FSA and theAEBC. The Cabinet Office/Office of Science andTechnology have issued a document, The Advisoryand Regulatory Framework for Biotechnology:Report from the Government’s Review May 1999,which summarised the 17 committees operating inthe area of biotechnology prior to the establishmentof the FSA and the AEBC. However, given thecomplexity of the regulations, the Royal Societyrecommends that an authoritative, easy-to-understand handbook be produced by one of therelevant government departments explaining tolaboratory scientists and other interested partiesexactly what controls are in place, whichorganisations are involved, and what the procedureis for obtaining permission to undertake research.

5.2 Potential hazards of GM animals

96 Possible hazards of GM animals include novel orincreased allergic reactions (for GM animals used infood or feed); possible toxic effects (from theproduction of toxins or other biologically activeproteins); adverse effects from a change in behaviouror in physical nature, eg, increased aggression;


5 Safety

changes in the ability of the animal to act as a humandisease reservoir (eg, the insertion of a novel viralreceptor); and effects on the ecosystem of release ofthe GM animal into the environment. The likelihoodof these happening and the possible impacts arediscussed in this section. Possible hazards of GManimals to human health and safety are coveredunder the Genetically Modified Organisms(Contained Use) Regulations 2000 (see Annex D fordetails).

97 Novel or increased allergic reactions are most likely tobe due to the introduction of a novel protein into aGM animal, milk or eggs. Every effort should bemade to avoid the introduction of known allergensinto animals intended for food use. Potential hazardsof novel proteins should be thoroughly investigatedbefore approval for human consumption (The NovelFoods and Novel Food Ingredients Regulations 1997)as medicine or food.

98 A GM animal that is susceptible to a human virusthrough insertion of a viral receptor could behazardous. The animal might act as a novel reservoirfor the human disease. Such considerations areaddressed by risk assessments under the GeneticallyModified Organisms (Contained Use) Regulations2000.

99 HO interest in GM animals ends when the animalsare killed. When an animal dies it is disposed of aswith all other GMOs (under GMO (Contained Use)Regulations); it would not enter the food chain.

100 One of the concerns associated with the introductioninto the diet of foods or medicines derived from GManimals is the possibility that genes from suchanimals may be taken up by consumers when eaten,and become part of their own genetic make-up.Despite the daily consumption of non-GM DNA fromfood in the diet, no evidence exists for the transfer ofintact animal genes into humans from the foodchain. Ninety-eight per cent of dietary DNA isdegraded to its constituent nucleotides by thedigestive enzymes in the gut. Although fragments ofDNA have been shown to survive this, GM DNA is nomore or no less a hazard to humans than any otherform of dietary DNA and the possibility of functionalgene transfer to humans via the food from a GManimal is remote.77

101 If a GM animal has very specific habitat requirementsits capacity to spread to other habitats is likely topose less of a concern than a habitat generalist, inthat its post-release distribution could be predictedwith greater accuracy. Freshwater or marine speciespresent specific hazards when released, because it isvery difficult to track their progress in water (andthere are similar problems with air-borne insects).

The potential ecological problems that could becaused by the release of GM animals into the wildpopulation are similar to those of releasing non-native species, which are dealt with under theWildlife and Countryside Act 1981.

102 An environmental concern is the escape of GM fishand their breeding with the natural population. Thisis unlikely if Atlantic salmon are farmed off thePacific coast of Canada or the USA because theywould not interbreed with the local endemic speciesof salmon. However, phenotypic changes due to thegenetic modification may provide the GM animalswith a competitive advantage over their wildrelatives for food, shelter, mates, and suitablebreeding sites. For example, their search forresources could disrupt the ecology of the naturalpopulation, especially if their larger size enhancedsuccess over smaller competitors. The heightenedcompetitive ability of GM salmon raises thepossibility that any escaped animals could readilycompete successfully in the wild, raising concernsover their impact on the ecosystem. Manycommunity interactions are not well understood atpresent. By introducing an organism with an alteredphenotype, the interactions of the species within anecosystem could be disrupted. However, theincreases in the metabolic demands of such fishcould also decrease their viability under naturalconditions. They may also be at greater risk frompredators. A recent study showed that growth-hormone-treated trout foraged closer to the water’ssurface, ate more food and resumed feeding earlierafter simulated attacks from a model heron. In otherwords, their motivation to feed overcame theircautious behaviour. Such behaviour would increasethe susceptibility to aerial predation. Predation mayhave been a factor that selected against high growthhormone secretion in wild fish.46

103 Successful breeding between GM animals and wildrelatives could result in a change to the genomes ofthe wild stocks. The severity of such an outcomewould depend on the genetic modification, thefrequency of successful mating and the fate of theoffspring. In some species of fish larger males have agreat advantage over smaller competitors formating. However, under aquarium conditions GMfish are more likely to die before reaching sexualmaturity. This might mean that such fish mate moresuccessfully but have a lower survival rate, drivingthe population to extinction. Coastal aquaculture isalready a cause for ecological concern because ofhabitat modification, nutrient pollution, spread offish disease and the escape of farmed fish.

104 At present, GM salmon are not sterile, but were thisto be a requirement before commercial licences areprovided, then creating sterile salmon would be


relatively simple. If salmon eggs are subjected to heator pressure shock shortly after fertilisation they retainan extra set of chromosomes. These triploid fish donot develop normal sexual characteristics and thefemales are sterile.

105 Despite the potential for sterilising GM fish, theRoyal Society of Canada, in its recent report onbiotechnology and food,80 concluded that theconsequences of genetic and ecological interactionbetween GM and wild fish were uncertain as was theutility of attempting to render GM fish sterile. Inparticular, the Royal Society of Canadarecommended a moratorium on rearing GM fish inaquatic net-pens, with approval for commercialproduction being conditional on rearing of the fish inland-locked facilities. The Royal Society endorses thisrecommendation.

106 The escape of GM mice is less likely than the escapeof fish. The main concern is not with accidentalrelease but with sabotage. For humans, the risk tothe population from the generation of GM mice,although not easily quantifiable, is finite. One riskarises through the spread of undesirable genes (orprotein in the case of prions) within the wild mousepopulations. This risk is minimal, given the ease ofcontainment of experimental mouse colonies andthe low degree of mating between wild andlaboratory strains of mice. Also, many GM mousemutations affect essential biological processes invivo, such that survival in the wild is unlikely. Atpresent the HSE’s regulations stipulate thatemergency plans in the event of unintended escapemust be in place if such a potential escape is deemedto have potentially serious effects. The Royal Societyrecommends that the risk assessment should requireall laboratories at which work on GM animals iscarried out to have emergency plans in the event ofaccidental release.

107 The potential human health and safetyconsequences of GM animals must be notified whena scientist applies for permission to work on or createGM animals. An environmental risk assessment isalso carried out but is not accompanied by acorresponding requirement to notify the competentauthority under the Environmental Protection Act1990 (Part VI) of any potential environmentalhazards should there be accidental (or indeed adeliberate and illegal) release. The Society isconcerned that, without such a requirement, nocentral source for data on environmental riskassessments will be available and no long-termmonitoring of safety is possible.

108 A special case of the above occurs when the aim ofthe release of GM animals is to replace a wildpopulation with the GM variant. This is the goal of

‘refractory’ strategies for controlling insect-bornediseases such as malaria (see section 4.8). The bestway to achieve population replacement is muchdebated. The genetic modification, though desirableto humans, is unlikely to increase the fitness of theinsect in the wild, and so is unlikely to spreadnaturally through the population on release. Theideal strategy for driving a beneficial (to humans)gene through a wild population would becontainable, reversible and repeatable without limit,in case the pathogen develops ‘resistance’ to thegenetic change or better insect variants becomeavailable. The simple strategy of repeatedly releasinglarge numbers of GM insects into an area fits thesecriteria but is expensive and impracticable for somespecies and areas. Alternative strategies focus onlinking the beneficial genes to a system that iscapable of driving itself through a population, suchas an autonomous transposon (see next paragraph)or endosymbiotic bacterium.

109 An autonomous transposon is a small section ofgenetic material that is capable of jumping from onechromosomal position to another. This propertyallows the transposon to be inherited by a highproportion of the progeny of an individual carryingthe transposon and so eventually spread through apopulation by vertical (parent to offspring)transmission. It also allows the possibility ofhorizontal transmission between organisms andspecies and of inserting itself into the genome.Transposons are very common in bacteria, fungi,plants and animals and horizontal transfers of thesemobile elements occur repeatedly and naturally,though infrequently (eg, at least 11 events among 18species over 3 million years for the so-called Pelement, which exists in Drosophila).88

110 In principle, release of a very small number of insectscontaining transposons would be capable of drivingthe beneficial genes through the entire globalpopulation of the insect. Unfortunately, it is not clearhow to ensure that the beneficial genes remainlinked to the mobile section of DNA during thespread through the population. Research on suchdrivers poses a very special threat to the environmentin that accidental release of a single individualcarrying such a driver could in principle modify thegenomes of the wild species on a global basis. Thisirreversible global conversion has been observed inthe case of the natural invasion of the P element intoDrosophila melanogaster populations during the20th century. There is also a remote possibility thatsuch an element might also spread to an unintendedspecies. Most of the proposed autonomoustransposons are likely to have extremely broad hostranges, so the species limits of such horizontaltransfer are not clear. The potential consequences ofthe release of such a genetic element into a


population are unclear and the Society considers thatmore research is needed before such a release can becontemplated.

111 The Royal Society recommends that thosedeveloping policy to implement the regulations

should pay particular attention to ensuring that thedevelopment of GM animals carrying autonomouselements is restricted to those species that have nolocal wild population and for which local climatic orother conditions prevent the possibility of escapedindividuals establishing themselves in the wild.


112 The potential benefits of causing the geneticmodification are great but so too may be the costs.The hazards to human health and to theenvironment have already been considered, butwhat of the welfare costs to the animals? This issueraised the biggest response from those whoresponded to the Society’s press release (see AnnexesA and B). It is the subject of several other studies,such as the ones currently underway by theBVAAWF/FRAME/RSPCA/UFAW and the AnimalProcedures Committee of the Home Office. Annex Dalso deals in some detail with the legislative controlsfor animal welfare in the UK.

113 Pain and suffering are at the forefront of publicconcern about animal welfare and an assumptionthat it can and will be assessed is embodied inlegislation in the United Kingdom about the use ofanimals in research, care of domestic pets and farmanimals, and much else. Pain and suffering aresubjective experiences. How may they be measured?The science of animal welfare is concerned with theorderly application of method to questions about thestates of individuals. Considerable progress has beenmade in clarifying the methods of welfareassessment. Assessments may be based on studyingthe physiology of the animal; the response tosituations that might be subjectively unpleasant tothem;22 the animal’s state as regards its attempts tocope with its environment;11 and the animal’sfunctional requirements in relation to its survival andreproductive success.2,3,23,99 When an animal doesnot behave as humans do in the same circumstances,this may well reflect differences in its naturalrequirements, its evolutionary history and the detailsof its social life. Therefore, assessments of sufferingwill also depend on good observational data aboutthe natural behaviour of the species in question, itsday-to-day needs, its vulnerability to damage and theecological conditions in which it lives.

114 A variety of approaches is more likely to provide areliable assessment of welfare than a singleapproach.3, 53,100 A multi-pronged approach is alsomore likely to reflect the various classes of problemthat lie behind a concern for the quality of ananimal’s life such as whether or not it is harmed,whether or not it is able to cope with its environmentand assessment of its psychological state.28

Judgements on each of these may play a supportiverole in assessing whether the welfare of an animal ispoor.

115 Species and individuals vary both in the methods thatthey use to try to cope with adversity and in themeasurable signs of failure to cope. A single welfare

indicator could show that welfare is poor, butabsence of an effect on one indicator of poor welfaredoes not mean that the welfare is good. Forexample, if the major effect of a manipulation was abehavioural abnormality or an increase in diseasesusceptibility but only growth rate was measured,the assessment of welfare would be misleading. Itmay be obvious from a preliminary study ofmorphology, or a clinical examination, whichmeasurements of function or of pathology are likelyto be most relevant. A comprehensive view of thewelfare may require application of the main methodsmentioned here. Hence a graded approach could beused, with initial studies made using simple cage-side, clinical or morphological measurements, thesecond stage involving more detailed studies andfinally specific studies aimed at particular welfareconcerns. The first or second stage may be sufficientto identify a severe problem or to pinpoint areas formore detailed study. In the case of a GM animal, athird stage study might be especially importantbefore release of the animal for general use orwidespread laboratory use.

116 Welfare issues are raised in the preparation of GManimals. The techniques used in mammals includeadministration of drugs to donor female animals, inorder to induce super-ovulation, followed by timedmatings and collection of fertilised eggs. After theyhave been genetically manipulated in vitro, themodified embryos are then implanted surgically intosurrogate mothers.

117 Both induction of super-ovulation and surgicalimplantation are established techniques, whichincreasingly are employed in selective breeding offarm and laboratory animals. While surgicalimplantation is carried out under generalanaesthetic, it can cause post-operative pain, andsuper-ovulation can cause discomfort. In both cases,appropriate analgesic should be administered in theinterests of good welfare. Preparation of surrogatemothers involves mating them with sterile males toproduce a pseudo-pregnancy, and the males musttherefore undergo vasectomy under generalanaesthetic. Sometimes, the donor female animalsare mated when very young, and this can bestressful.41

118 Aside from the direct effects of the techniquesinvolved, fetal death can occur during pregnancy,and some additional deaths can occur post-natally. Itis uncertain at what stage in development fetusescan experience pain and distress, or how far thewelfare of the mother is compromised by fetal death.However, in the larger farm animals it is known that


6 Welfare

miscarriages cause distress to the mother. Lossesduring production mean that relatively largenumbers of donor and recipient animals must usuallybe used in order to produce a relatively low yield ofGM animals.

119 A report by the Boyd group7 (Boyd Group, 1999 –available at http://www.boyd-group.demon.co.uk/genmod.htm) highlights thefact that data on mortality rates and ages at whichdeath occurs during production of GM animals arehard to find.

120 With respect to genetic modification, a largelyhypothetical concern is that the introduction of agene from a very different type of organism may leadto unforeseen interactions in development and theemergence of animals that have serious welfareproblems. Strange interactions can arise indevelopment as a result of conventional plant andanimal breeding or by changing the environment inwhich the organism typically grows. This was theconcern of many of those who responded to theSociety’s press release (see Annexes A and B). Acommon theme was that genetic modification hadhighly unpredictable effects on the phenotype of theanimal. Uncertainty might arise because ofdifficulties in determining the location of theinsertion of the transgene, with consequent lack ofcontrol over the expression of the gene. Expressionmight depend on the genetic background with bigdifferences between different inbred strains andbetween species, and expression might vary greatlyfrom one organ to another. Bizarre patterns ofinheritance might arise from lack of integration intoa chromosome. These points raise an importantquestion. While animals are remarkably wellbuffered by developmental mechanisms against thevagaries of the environment and against naturallyoccurring changes in their genomes,106,107 are theyequally well buffered against the effects ofintroducing genes from other organisms? As thingsstand, no clear evidence suggests that they are not.In part this is testament to the remarkable self-righting properties of organisms. In part it may bedue to the similarities of genomes in all organisms.

121 Surprisingly, the effects of making particular geneticchanges are often very difficult to detect, and evenwhen they can be measured, the welfare costs areseemingly non-existent or negligible. However,genetic modification by the selective removal oraddition of genes does not guarantee that theeffects will be benign. Indeed, the benefits tomedical research may arise precisely because theadult characteristics are the same as those as in a

diseased human being. A much quoted case inwhich enhanced expression of growth hormone wasengineered is the Beltsville pig.65 This pig had grossabnormalities. Such abnormalities are also producedby artificial selection as in broiler chickens.23 Theeffects may be more quickly produced by geneticmodification but they can be also be more quicklyrecognised. Moreover, the targeted geneticmodification approach is likely to be morepredictable than the more general approach ofsubjecting the whole genome to radiation or tochemical mutagens. That said, the effects of geneticmodification produced by any means may not beapparent at all stages of life so the animal must bestudied at different stages, including the oldest agelikely to be reached during usage. Some effects maybe evident in the second generation but not in thefirst, which is why it is current practice to continue tostudy modified animals for at least two generations.

122 The targeting of genes in order to model humandisease states or change patterns of growth cangenerate serious welfare problems. That said,intensive behavioural studies have been conducted onGM sheep to monitor any adverse welfareimplications and these have found very little differencebetween animals that have been genetically modifiedand those that have not.42 Van der Meer comparedmice genetically modified to produce a hormone withmice that had not been modified.104 While the GMmice were lighter, differences in behaviour were veryslight and signs of adverse welfare were not detected.In general, the few studies available do not showsevere welfare effects in the GM animals studied. Theeffects of genetic modification may only be apparentin more stressful environments such as thoseproduced by greater competition for food or extremesof temperature. More information should be soughton the presence and extent of any adverse welfareeffects of producing and using GM animals. Also thesuitability of currently available methods of assessingwelfare of laboratory animals for all categories of GManimals should be investigated.

123 Although genetic modification is capable ofgenerating welfare problems, in the view of theRoyal Society, no qualitative distinction in terms ofwelfare can be made between genetic modificationusing modern genetic modification technology andmodification produced by artificial selection,chemicals or radiation. Indeed, the targetedcharacter of modern genetic technology mayprovide fewer welfare problems than oldertechniques. Furthermore, it may identify morerapidly areas of concern such as the ill-effects ofenhanced growth.


124 The Animal Procedures Committee has recentlycompleted a consultation on cost–benefitassessment with respect to the Animal (ScientificProcedures) Act 1986 that specifically considered theuse of GM animals, and the Royal Society welcomesthe attention it is paying this issue. While acost–benefit approach lies at the heart of mostassessments of whether or not genetic modificationof an animal is justified, this is an area of thoughtsurrounded by much confusion. Before dealing withthe specific questions raised by genetic modification,it is worth making two general points. First, costs andbenefits are generally measured in different ways;therefore, the metaphor of weighing one against theother is misleading if used in a precise sense.‘Weighing’ is meant in the rather vague sense ofcomparing one outcome with another. The point isnot trivial because judgements must depend on aconsensus and cannot be derived by any precisemethodology. Second, what are presumed to becosts and benefits will themselves be heavilydependent on value systems that may sometimes becompatible with others but often are not.

125 Many, sometimes contradictory, positions underlieperceptions of the costs of using animals in scientificresearch. Examples of some of these are as follows.

• The only animal species that suffers is the human.Nevertheless, some people feel that treatment of otheranimals is important because of the way it affectsattitudes to fellow human beings. They are scepticalabout consciousness in animals other than humans, buttake the view that human readiness to empathise withother animals means that if such feelings in thisdirection are denied they will also be denied to humans.

• Animals should be protected because they arebeautiful and much loved. The same view wouldapply if the object in question were a magnificentoak tree or an inanimate work of art such as awonderful picture. A related issue is that animalsshould be respected and not tampered with in anyway by humans.

• The issue of how animals are treated is all aboutrights. One view is that each animal has the right tolife and humans have no business taking such a rightaway from it. Others consider that a right cannot beabstracted from its social context and even humansare required to waive in times of war what theywould normally regard as their most precious right ofall, namely their right to life. Those who disagree that

rights are part of the relationships with fellow humanbeings must answer how far they are prepared togeneralise from humans to less complicated beings.

126 Not granting rights to animals does not mean thathumans have no responsibilities for the animals intheir care. The dominant view about animal welfareis that the more complicated animals at least dosuffer in much the same way as humans do.

127 It is not easy to be wholly consistent on ethicalmatters and many people are as confused about theuse of animals in research as they are about the useof animals for food and clothes. A MORI pollconducted for the Medical Research Council55

demonstrated that most people refer to ‘cruelty’when asked what they think about animalexperimentation, but that most people endorseanimal experimentation for medical purposes. It islikely, too, that many people hold at the same timedifferent beliefs about why animals should not beharmed. Nevertheless, it helps to know what cost isbeing talked about, particularly when cost–benefitanalysis is considered. When weighing up thebenefits of genetic modification for, say, medicalresearch against the welfare costs to the animal, theRoyal Society believes that precisely the samecost–benefit considerations apply as to all otheruses of animals in research. Nevertheless, geneticmodification is regarded as being disrespectful tothe animal by some,73 and as a sensible advance intechnology by others. It is doubtful whether anycompromise can be found between the two groupsholding such divergent views. For those who holdthat nothing would justify genetic modification ofan animal, cost–benefit analysis is meaningless. TheRoyal Society believes that since minimising animalsuffering is the main concern of most people, it ispossible to avoid deadlock by minimising sufferingat the same time as maximising the gain tomedicine, agriculture and fundamentalunderstanding.

128 Deriving a ‘balance’ between cost and benefit is noteasy at the best of times because the two are notmeasured in the same terms. What is done inpractice is to find a space in which there is aconsensus that the costs are acceptably low and thebenefit is sufficiently great. The moral tensionremains, of course, and the boundary between whatis and what is not acceptable undoubtedly changes.


7 Weighing benefits against burdens

129 The advent of genetic modification over the last20–30 years has revolutionised the development ofnew varieties of plants. Tobacco was first geneticallymodified in 1983, but with the advent of GM cropssuch as cereals and soya, intended for food use, GMproducts have become a focus for concern andcontroversy. Similar techniques have also been usedto produce GM animals (the first GM mouse wasproduced in the early 1980s), and this technologyhas now been applied to many animals includingcattle, pigs, sheep, poultry, frogs, fish and fruit-flies.Genetic modification of animals has aroused similarconcerns to those associated with GM plants, withthe additional welfare and ethical issues thatsurround any work with animals. It is important thatsuch concerns are addressed seriously if society is tobenefit from new developments. It is also importantthat public debate about GM animals is informedwith sound evidence.

130 Application of GM technology to animals can beused in medical research to create models of humandisease. Such models help elucidate diseasepathways and allow assessment of new therapies.Many critics of genetic modification questionwhether animals model human disease states. If theyare correct, the supposed benefit of using GManimals would be greatly reduced. This reportpresents evidence that a strong scientific case can bemounted for using such animals in order tounderstand human and animal disease.

131 The information from the Human Genome Project haspresented us with a genome of 30,000–40,000 genes,about which very little is known. In other words, oncethe DNA sequence of a gene is known, the next step isto find out what it does. Analysing gene function is anarea in which the use of GM animals, particularly GMmice, is likely to rise significantly. This is because bymodifying a gene, scientists can learn which biologicalsystems are affected, and thus they can pinpoint whatthe gene does.

132 The aims in creating GM animals for agricultural usemay be set for a variety of reasons. One importantgoal is to introduce genes that confer resistance toparasites and pathogens, such as the virus causingfoot and mouth disease in sheep, pigs and cattle.Creating disease-resistant animals is especiallyimportant for the farmers in the developing world.The Society recommends that research efforts on thistechnology are addressed with particular urgency.Cooperation between the public and private sectorsis needed and must involve a willingness to shareknowledge, currently restricted under patent andlicensing agreements.

133 An important agricultural goal is to introducedesirable alterations in growth rates or feedconversion efficiency. Yet another is change in thecomposition of meat in order to produce eitherleaner meat or to enhance anti-microbial propertiesof milk for newborn animals. Much of thetechnology is at an early stage and much moreresearch will be needed before developments aimedat growth modification have commercial application.Furthermore, detailed analyses of the genetic controlof normal muscle growth, development andphysiology in animals are needed so that anygenetically altered trait is consistent with goodwelfare, in both GM animals and also in animals bredvia selective breeding techniques. The Society hasrecently recommended that the MAFF should fundresearch into the welfare implications of GM animalsfor agricultural use. It is likely to be at least a decadebefore large animals with modified or deleted genesof commercial value have been evaluated andapproved by the various regulatory bodies.

134 All GM animals developed in the UK, whatever theirintended application, must be assessed by acomprehensive framework of committees andlegislation that regulate and provide advice on GManimals. Policy in this area is overseen by the newAgriculture and Environment BiotechnologyCommission (AEBC), which is an independent body,and the Royal Society welcomes the setting-up of asub-group of the AEBC that is looking at currentlegislation. This area is complex and needs carefulexamination to ensure there are no conflicts andgaps in the legislation. The Cabinet BiotechnologyCommittee is responsible for coordination ofgovernment policy on legislation. Given thecomplexity of the regulations, the Societyrecommends that an authoritative, easy-to-understand handbook be produced by one of thegovernment departments explaining to laboratoryresearchers exactly what controls are in place, whichorganisations are involved, and what the procedureis for obtaining permission to undertake research.

135 While new strains are being developed, researchworkers are required to count as experimental thoseapparently normal animals governed by the Animals(Scientific Procedures) Act 1986, which were in thesame litter as ones that have been geneticallymodified. This is because they might exhibit covertchanges that do not necessarily become apparentuntil a subsequent generation. The countingprocedure means that, until inbred lines of geneticmodification animals have been produced, thenumbers of animals used in genetic modificationresearch are likely to rise. The Royal Society


8 Conclusions and recommendations

recommends that the Home Office, in consultationwith researchers, should develop criteria for moreaccurate recording of GM and non-GM offspring ofthose animals covered by the Act.

136 Possible hazards of GM animals include novel orincreased allergic reactions and toxic effects if theyare eaten, changes in behaviour of the animals suchas increased aggression, changes in the ability of theanimals to act as a human disease reservoir, andimpact on the ecosystem if the animals are releasedinto the environment. The likelihood of thesehappening is considered to be relatively low butcertainly should not be neglected.

137 The Royal Society recommends that the riskassessment should require all laboratories at whichwork on GM animals is carried out to have emergencyplans in the event of accidental release. The potentialhuman health and safety consequences of GM animalsmust be notified when a scientist applies for permissionto work on or develop GM animals. An environmentalrisk assessment is also carried out but is notaccompanied by a corresponding requirement to notifythe competent authority under the EnvironmentalProtection Act 1990 of any potential environmentalhazards should there be accidental (or indeed adeliberate and illegal) release. The Society is concernedthat, without such a requirement, no central source fordata on environmental risk assessments is available andno long-term monitoring of safety is possible. TheSociety also endorses the recommendation of theRoyal Society of Canada for a moratorium on rearingGM fish in aquatic net-pens, with approval forcommercial production being conditional on rearing ofthe fish in land-locked facilities.

138 The Royal Society recommends that thosedeveloping policy to implement the regulationsshould pay particular attention to ensuring that theproduction of GM animals carrying autonomousgenetic elements is restricted to those species thathave no local population and for which local climaticor other conditions prevent the possibility of escapedindividuals establishing themselves in the wild.

139 The benefits of causing genetic modification inanimals may be great, but so too may be the welfare

costs. Such costs to the animals raised the biggestresponse from those who responded to the Society’spress release and are the subject of several otherstudies underway at present. This report summarisesthe issues of concern and concludes that moreinformation should be sought on the presence andextent of any adverse welfare effects of producing andusing GM animals. Also, the suitability of currentlyavailable methods for assessing welfare of laboratoryanimals for all categories of GM animals should beinvestigated. Although genetic modification iscapable of generating special welfare problems, in theview of the Royal Society, no qualitative distinction interms of welfare can be made between geneticmodification using modern genetic modificationtechnology and modification resulting from artificialselection, chemicals or radiation. Indeed, the targetedcharacter of modern technology may provide fewerwelfare problems than older techniques, and it mayidentify more rapidly areas of concern such as the ill-effects of enhanced growth.

140 Some would regard genetic modification asunacceptable under all circumstances because such aprocedure is disrespectful to the animal or violates itsrights. However, many others would regard theappropriate stance as being to minimise thesuffering and maximise the gain to medicine,agriculture and fundamental understanding. This isthe position adopted by the Royal Society.

141 The Royal Society concludes that the development ofGM animals has been hugely beneficial in manyareas, not least into research on the causes andpossible treatments of disease. It also has thepotential to bring about many other benefits, butmany serious concerns remain about welfare, andhealth and safety issues that need to be addressed ifthese benefits are to be realised. Continued research,funded in part from public sources, and with theresults made openly available, is essential if theseuncertainties are to be properly addressed and therisks understood. The Royal Society recommendsthat those involved in GM technology, whether inthe development of legislation or in the applicationof the scientific developments, should engage in anopen and frank debate with the public and recogniseconcerns about this issue.


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Royal Society investigates use of GM animals

The Royal Society is responding to the public’s concernsabout genetically modified (GM) animals and isundertaking an independent study into their use inmedicine and agriculture, it was announced today (8 June2000).

A working group of eight scientists has been set up toreview the scientific progress, advise on any future policyimplications and to issue a report later this year.

Professor Patrick Bateson FRS, the chairman of theworking group, said, ‘The technology of GM animals hasprogressed rapidly in recent years and has led to concernamongst the media and general public about possiblerisks to humans and the environment as well as welfareconcerns for the animals themselves. The Royal Societywishes to facilitate the debate about GM animals byproviding the public and policy makers with anindependent overview of the scientific evidence. Wewelcome submissions by 30 June from interested partieswho have evidence on either the costs or the benefits ofcreating and using GM animals.’

The working group will: • Outline the background science to date relating to

the medical and agricultural applications of GManimals, where ‘animal’ includes birds, mammals,fish and insects

• Consider likely future research in these areas• Consider current legislation governing the uses of

GM animals.

The working group will not be covering xenotransplantation(transplantation from another species into humans) in detailin this study.

Currently the main medical application for GM animaltechnology is the use of animal models for human disease,eg mice with cystic fibrosis, models for studying the spread ofBSE into humans, etc. Research is also underway into so-called ‘pharming’, where for example an animal isengineered to secrete medically valuable proteins in its milk.

Possible agricultural applications include animals engineeredto withstand drought, salmon engineered to grow faster andlarger than their wild counterparts, or mosquitoesengineered to be resistant to malaria to counteract thespread of the disease in developing countries.


Annex A Press release

Issued at the start of the project to announce the study and to request submissions from interested partiesEmbargoed until 00:01, Thursday 8 June 2000

The following organisations contributed to thestudy, either by responding to the Press Release callfor contributions or in some other way.

National Farmers Union Biotechnology and Biological Sciences Research Council Food Standards Agency Medical Research Council Office of Science and TechnologyHome Office Advisory Committee on Novel Foods and Processes Scottish Executive Agriculture and Environment Biotechnology CommissionAdvocates for AnimalsBritish Union for the Abolition of VivisectionDr Hadwen TrustFarm and Food SocietyFarm Animal Welfare CouncilFund for the Replacement of Animals in Medical

ExperimentsRoyal Society for the Prevention of Cruelty to AnimalsUK Life Sciences CommitteeUniversities Federation for Animal Welfare

The Society acknowledges the help of the following in theproduction of this report:

Dr Michael Appleby, Institute of Ecology and ResourceManagement, University of Edinburgh;

Reverend Professor Michael Reiss, Institute of Education,University of London;

Baroness Onora O’Neill, Newnham College, Cambridge;

Professor John Webster, School of Veterinary Science,University of Bristol.


Annex B List of respondees


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Regulations governing the use of animals in research, andthe use and development of GM animals, are made at EUand national level. If EU directives are put into place, theneach Member State has to implement these Directives byindividual regulations. A table summarising EU and UKlegislation can be found at the end of this Annex.

1 Development of GM animals

In the UK, all scientific work with animals must belicensed under the Animals (Scientific Procedures) Act1986, which is administered by the Home Office. The Actrequires the licensing of any experiment or other scientificprocedure carried out on living, protected animals whichmay cause them pain, suffering, distress or lasting harm.It protects all vertebrate species (except man), that ismammals, reptiles, birds, amphibians and fish, and oneinvertebrate species, Octopus vulgaris. This definitionincludes fetal, larval or embryonic forms from the stage indevelopment when (a) in the case of a mammal, bird orreptile, half the gestation or incubation period for thespecies has elapsed or (b) in any other case, when itbecomes capable of independent feeding.

In the context of GM animals, Section 2(3) of the Act is ofprime importance. This section states that anything donefor the purpose of, or liable to result in, the birth orhatching of a protected animal is also a regulatedprocedure if it may have the effect of causing pain,suffering, distress or lasting harm.

Two aspects of the production of GM animals requireconsideration: (i) the insertion of DNA into the germlineand (ii) the subsequent breeding of animals carrying thedesired characteristic. Initial production of GM animals istherefore regarded as a Regulated Procedure and must becarried out under the authority of a Project License and aPersonal License. Breeding of GM animals is also aregulated procedure under the terms of the 1986 Act,and again project and personal license authorities areneeded. Genetically modified animals that can bedemonstrated not to be prone to pain, suffering, distressor lasting harm as a result may be discharged from thecontrols of the 1986 Act, providing the Secretary of Statefor the Home Office is satisfied that this condition is met.Decisions will be taken on a case-by-case basis.

The Act applies throughout the United Kingdom. Forwork taking place in England, Scotland and Wales theHome Office issues licenses under the Act on behalf of theHome Secretary. The Home Office has an Inspectorateconsisting of qualified professional staff who examineand advise on all applications for authorities under the1986 Act. They also inspect establishments and workalready licensed under the Act.

The Animal Procedures Committee (APC) provides theHome Secretary with independent advice about thislegislation and his functions under it. The members of theCommittee are experts from a wide variety ofbackgrounds, appointed by the Home Secretary(http://www.apc.gov.uk/).

Initial work to develop a GM animal starts in the laboratorywith transfer of individual genes. In the UK, each laboratoryinvolved in genetic modification must be registered underthe Genetically Modified Organisms (Contained Use)Regulations 2000. Registration involves submitting anotification to the Health and Safety Executive (HSE)describing the work to be carried out. Under the regulations,each centre carrying out genetic modification must have aGenetic Modification Safety Committee to advise on andreview notifications. Once submitted, each notification isreviewed by the Health and Safety Executive and othergovernment departments and devolved administrations(including the Department of the Environment, Transportand the Regions (DETR), the Ministry of Agriculture, Fisheriesand Food (MAFF), the Department of Health (DH), theScottish Executive (SE) and the National Assembly for Wales(NAW) as appropriate). An independent advisory committee,the Advisory Committee on Genetic Modification (ACGM),may also be consulted. Laboratories carrying out geneticmodification work are open to inspection by HSE specialistInspectors to ensure compliance with the Regulations.

The Genetically Modified (Contained Use) Regulations2000 require all work with GM animals to be subject to arisk assessment for effect on human health and safety. Aspart of this the GM animal is assessed on the basis ofwhether it is more likely to cause harm to humans thanthe non-modified parental organism. Any animal thatposes a greater risk of harm to human health and safetythan the non-modified equivalent must be notified to theHSE under the Contained Use Regulations 2000 beforework can be commenced.

Under the Contained Use Regulations 2000, GM micro-organisms are also subject to a risk assessment for impacton the environment, but GM animals (and plants) are not.Environmental protection legislation requires that thisassessment be carried out.

The Environmental Protection Act 1990 (EPA1990)requires risk assessment of all GMOs. The GeneticallyModified Organisms (Risk Assessment) (Records andExemptions) Regulations 1996 are made under theEPA1990. The EPA1990, together with the associatedRegulations, requires that anyone keeping GM animals(or plants) must carry out an assessment of the risks to theenvironment. The assessment must include hazardsarising from the escape of the animals (or plants), and therisk of such hazards occurring. The assessment enables


Annex D Summary of statutory regulations pertaining to GM animals

the keeper of the GM animal (or plant) to put in placesuitable containment measures to minimise damage tothe environment resulting from escape. Records of theseassessments must be kept for 10 years, but do not needto be reviewed unless requested by an Inspector from theHSE when visiting the site.

Further information on the above legislation can be foundon the following web pages:Home Office, APC –http://www.homeoffice.gov.uk/ccpd/aps.htm;HSE, ACGM –http://www.hse.gov.uk/hthdir/noframes/acgmcomp/acgmcomp.htm.

2 Applications of GM animals

Under Part VI of the EPA1990 it is an offence todeliberately release any GMO into the environment, or toallow it to escape, without prior consent from theSecretary of State.

If the GM animal is intended to be released outside alaboratory or other ‘contained’ facility in the UK, it musthave received consent under the Genetically ModifiedOrganisms (Deliberate Release) Regulations 1992 (asamended 1995 and 1997). Applications for consent mustdescribe the GMO, and give details of the proposed release,and must contain a full risk assessment for the effect onhuman health and safety, and impact on the environment.Applications are submitted to the Department of theEnvironment, Transport and the Regions (DETR), andreviewed by DETR and other Government departments anddevolved administrations (including HSE, MAFF, SE, NAW,etc). Each application is also reviewed by anotherindependent committee of experts, the AdvisoryCommittee on Releases to the Environment (ACRE)(http://www.environment.detr.gov.uk/acre/). To date noapplications to release or market a GM animal in the EUhave been made.

The Food Standards Agency (FSA) is the authority in theUK that determines the safety of transgenic livestock forfood consumption. So far no animals have beensubmitted for approval either to the FSA, or to theequivalent body in the USA the Food and DrugAdministration (FDA). The FDA’s guidelines would requiretransgenic farm animals for food consumption todemonstrate the safety of: the transgene and anyregulatory or additional genes or parts of a gene; theexpressed gene in the tissues or product; and otherconsequences of transgene expression.

3 Animal welfare

Under the Animals (Scientific Procedures) Act 1986, GManimals are not considered any differently from any otherlaboratory or domestic species. They are subject to thesame Regulations and Codes of Practice as any otheranimal in a similar situation. In laboratory species, thecontrols on the breeding and supply of animals for use inscientific procedures under the 1986 Act will apply.

The welfare of domestic animal species is subject to theProtection of Animals Act 1911 (in Scotland 1912), whichmakes it an offence to cause unnecessary suffering to anyanimals. The Agriculture (Miscellaneous Provisions) Act1968 makes it an offence to cause unnecessary pain ordistress to any livestock on agricultural land. Codes ofPractice for the welfare of most species of farm livestock(cattle, sheep, pigs, poultry, etc) are issued under the1986 Act and published by the MAFF and the Scottishand Welsh Departments. The Transit of Animals Orders(1973 and 1975) are concerned with the welfare ofanimals in transit. If a GM animal is fit to travel and istransported in accordance with the provisions of thewelfare legislation, then no action would be taken. If,however, the animal’s condition, through being GM, wereto render it unfit in any way, then its movement couldconstitute an offence.



Titl

e o

f leg

isla

tio

nN

ote

sLe

ad g

ove

rnm

ent d

epar

tmen

t

UK

Hum

an F

ertil

isat

ion

and

Embr

yolo

gy A

ct 1

990.

No

dire

ct re

latio

n to

wor

k w

ith G

M a

nim

als,

but

cov

ers

Dep

artm

ent o

f Hea

lth.

licen

sing

and

mon

itorin

g of

clin

ics

prov

idin

g: in

fert

ility

tr

eatm

ent;

sto

rage

of h

uman

spe

rm a

nd e

ggs;

and

rese

arch

usin

g hu

man

spe

rm, e

ggs

and

embr

yos.

Med

icin

es A

ct 1

968.

Cov

ers

som

e as

pect

s of

xen

otra

nspl

anta

tion

(cel

l the

rapi

es, g

ene

Dep

artm

ent o

f Hea

lth.

Med

icin

es fo

r Hum

an U

se (M

arke

ting

Aut

horis

atio

ns, e

tc)

ther

apie

s in

volv

ing

viab

le a

nim

al ti

ssue

).Re

gula

tions

199

4.

Gen

etic

ally

Mod

ified

Org

anis

ms

(Con

tain

ed U

se)

Prot

ects

hum

an h

ealth

and

saf

ety

and

envi

ronm

ent f

rom

GM

Os

For C

onta

ined

Use

Reg

ulat

ions

200

0:Re

gula

tions

200

0.us

ed in

‘con

tain

ed’ f

acili

ties.

All

deci

sion

s ba

sed

on s

cien

tific

/H

ealth

and

Saf

ety

Exec

utiv

e.En

viro

nmen

tal P

rote

ctio

n A

ct 1

990

(Par

t VI).

tech

nica

l ris

k as

sess

men

t.G

enet

ical

ly M

odifi

ed O

rgan

ism

s (R

isk

Ass

essm

ent)

(Rec

ords

A

dvis

ory

Com

mitt

ee –

Adv

isor

y C

omm

ittee

on

Gen

etic

Fo

r the

Env

ironm

enta

l Pro

tect

ion

Act

:an

d Ex

empt

ions

) Reg

ulat

ions

199

6 (a

men

ded

1997

).M

odifi

catio

n (A

CG

M).

Dep

artm

ent o

f the

Env

ironm

ent,

Tra

nspo

rt

and

the

Regi

ons

(Eng

land

); Sc

ottis

h Ex

ecut

ive

(Sco

tland

); N

atio

nal A

ssem

bly

(Wal

es).

Ani

mal

s (S

cien

tific

Pro

cedu

res)

Act

198

6 (r

evis

ed 1

993

Requ

ires

the

licen

sing

of a

ny e

xper

imen

t or o

ther

sci

entif

ic

Hom

e O

ffic

e.an

d 19

99).

proc

edur

e ca

rrie

d ou

t on

livin

g, p

rote

cted

ani

mal

s. A

lso

cove

rspr

emis

es u

sed

for b

reed

ing

cert

ain

anim

als.

Adv

isor

y C

omm

ittee

– th

e A

nim

al P

roce

dure

s C

omm

ittee

(APC

).

Gen

etic

ally

Mod

ified

Org

anis

ms

(Del

iber

ate

Rele

ase)

Pr

otec

ts h

uman

hea

lth a

nd s

afet

y an

d en

viro

nmen

t.

Dep

artm

ent o

f the

Env

ironm

ent,

Re

gula

tions

199

2 (a

men

ded

1995

and

199

7).

Requ

ires

anyo

ne in

tend

ing

to re

leas

e or

mar

ket a

GM

O to

Tr

ansp

ort a

nd th

e Re

gion

s.En

viro

nmen

t Pro

tect

ion

Act

199

0 (P

art V

I).ap

ply

to th

e Se

cret

ary

of S

tate

for c

onse

nt.

All

deci

sion

s ba

sed

on s

cien

tific

/tec

hnic

al ri

sk a

sses

smen

t.A

dvis

ory

Com

mitt

ee –

Adv

isor

y C

omm

ittee

on

Rele

ases

to

the

Envi

ronm

ent (

AC

RE).

The

Nov

el F

oods

and

Nov

el F

ood

Ingr

edie

nts

Regu

latio

ns 1

997.

Wou

ld c

over

GM

ani

mal

mat

eria

l int

ende

d to

ent

er th

e hu

man

Min

istr

y of

Agr

icul

ture

, Fis

herie

s an

d Fo

od.

food

cha

in. N

o ap

plic

atio

ns in

the

UK

to d

ate.

Adv

isor

y C

omm

ittee

– A

dvis

ory

Com

mitt

ee o

n N

ovel

Foo

ds a

nd P

roce

sses

(A

CN

FP).

Euro

pea

nM

edic

ines

Dire

ctiv

e (6

5/65

/EEC

).C

over

s so

me

aspe

cts

of x

enot

rans

plan

tatio

n (c

ell t

hera

pies

, ge

ne th

erap

ies

invo

lvin

g vi

able

ani

mal

tiss

ue).

Med

ical

Dev

ices

Dire

ctiv

e (9

3/42

/EEC

).C

over

s po

tent

ial x

enot

rans

plan

tatio

n m

ater

ial i

nvol

ving

the

use

of a

med

ical

dev

ice.

Con

tain

ed U

se G

enet

ical

ly M

odifi

ed M

icro

-org

anis

ms

Cov

ers

the

cont

aine

d us

e of

GM

mic

ro-o

rgan

ism

s.D

irect

ive

(90/

219/

EEC

) (re

vise

d 19

98),

supp

lem

ente

d by

D

irect

ive

2001

/203

/EC

.

Gen

etic

ally

Mod

ified

Org

anis

ms

(Del

iber

ate

Rele

ase)

C

over

s th

e re

leas

e an

d m

arke

ting

of G

MO

s.

Dire

ctiv

e (9

0/22

0/EE

C) (

to b

e re

peal

ed b

y th

e co

min

g in

to

No

appl

icat

ions

for G

M a

nim

als

in th

e EU

to d

ate.

forc

e of

Dire

ctiv

e 20

01/1

8/EC

in 2

001)

.


Titl

e o

f leg

isla

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nN

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sLe

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ent d

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Dire

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C) o

n th

e ap

prox

imat

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of la

ws,

C

over

s ex

perim

enta

l or o

ther

sci

entif

ic p

roce

dure

s w

ith a

nim

als.

regu

latio

ns a

nd a

dmin

istr

ativ

e pr

ovis

ions

of t

he M

embe

r St

ates

rega

rdin

g th

e pr

otec

tion

of a

nim

als

used

for

expe

rimen

tal a

nd o

ther

sci

entif

ic p

urpo

ses

(cur

rent

ly b

eing

up

date

d).

Cou

ncil

of E

urop

e Eu

rope

an C

onve

ntio

n ET

S 12

3 (1

986)

.Pr

otec

tion

of v

erte

brat

e an

imal

s us

ed fo

r exp

erim

enta

l or o

ther

Ra

tifie

d by

UK

1 Ju

ly 2

000.

scie

ntifi

c pu

rpos

es.

Cou

ncil

Regu

latio

n co

ncer

ning

nov

el fo

ods

and

nove

l foo

d D

efin

es a

nov

el fo

od a

s a

food

whi

ch h

as n

ot b

een

used

for

ingr

edie

nts

(EC

258

/97)

.hu

man

con

sum

ptio

n to

a s

igni

fican

t deg

ree

with

in th

e C

omm

unity

(and

falls

with

in a

num

ber o

f spe

cifie

d ca

tego

ries,

whi

ch in

clud

e G

MO

s).

Wou

ld c

over

GM

ani

mal

mat

eria

l int

ende

d to

ent

er th

e hu

man

fo

od c

hain

. No

appl

icat

ions

in th

e EU

to d

ate.

Cou

ncil

Dire

ctiv

e on

the

prot

ectio

n of

ani

mal

s ke

pt fo

rG

ives

gen

eral

rule

s fo

r the

pro

tect

ion

of a

nim

als

of a

ll sp

ecie

sfa

rmin

g pu

rpos

es (9

8/58

/EC

).ke

pt fo

r the

pro

duct

ion

of fo

od, w

ool,

skin

or f

ur o

r for

oth

erfa

rmin

g pu

rpos

es, i

nclu

ding

fish

, rep

tiles

of a

mph

ibia

ns. T

hese

ru

les

are

base

d on

the

Euro

pean

Con

vent

ion

for t

he P

rote

ctio

n of

Ani

mal

s ke

pt fo

r Far

min

g Pu

rpos

es. T

hey

refle

ct th

e so

-cal

led

‘Fiv

e Fr

eedo

ms’

as

adop

ted

by th

e Fa

rm A

nim

al W

elfa

re C

ounc

il.

alleles alternative forms of a gene which occupy the same position on achromosome

autonomous transposon small sections of DNA carrying a gene and other information, andcapable of integrating with the genome

carcinogenic cancer causing

cDNA a strand of DNA whose sequence is complementary to the strand inquestion

chimaera an animal that is a mixture of cells derived from two separate embryosfrom the same or different species

chromosome a large DNA molecular chain in the cell along which genes are located

DNA deoxyribonucleic acid, which is present in almost all living cells andcontains information coding for cellular structure, organisation andfunction

endosymbiotic an organism which lives inside another organism to the mutualadvantage of both

enhancer a sequence of DNA that increases the use of promoter sequences.Together they control transcription and hence expression of genes

enucleated a cell without a nucleus

epigenic epi = outside, caused by factors other than genetic

expression not all genes are active. When a gene is read and the product of thegene (a protein) is produced, the gene is said to be expressed.

gene the basic unit of heredity; an ordered sequence of nucleotide bases,comprising a segment of DNA. A gene may contain the sequence ofDNA that encodes one protein chain. Each animal has two similar ordissimilar copies (alleles q.v.).

genome the entire chromosomal genetic material of an organism

genotype the genetic make-up of an organism

genetic modification see definition in Annex C

heterozygous having one or more pairs of dissimilar alleles on correspondingchromosomes, ie, the two alternative forms of a gene for acharacteristic are different

homozygous having identical rather than different alleles in corresponding positionson homologous chromosomes. The two alternative forms of a gene fora characteristic are the same and therefore the organism will breed truefor that characteristic

horizontal transmission transmission of genetic information between organisms withoutreproduction


Annex E Glossary

mutagenic a substance causing changes in DNA

nucleus an organelle a (specialised structure) cell containing DNApeptide biologically important class of molecules that can exist separately or be

part of a protein

phenotype the appearance or other characteristics of an organism, resulting fromthe interaction of its genetic constitution with the environment

polygenic caused by many genes

promoter a region of DNA involved in binding the enzyme that reads the messageon the DNA

recessive condition a condition that requires two affected genes to be inherited, one fromeach parent, before causing a major change in the animal

reporter gene one that, when altered, signals its presence under examination

somatic of the body

stem cell one that has the capacity to renew itself as well as to produce morespecialised progeny

teratogenic a substance that causes prenatal abnormalities

totipotential a cell having the capability to form any cell (see stem cell)

transcription the process of reading DNA

xenotransplantation transplantation of tissues from one species to another


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