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ENVIRONMENTAL RISK MANAGEMENT AUTHORITY DECISION

Controls amended under S67A 27 March 2002.

Application code GMF99004 Original Decision 26 October 2000

Hearing date 6 and 7 April 2000Considered by Special Committee of the Authority appointed under

section 19(2)(b) of the Hazardous Substances and New Organisms Act 1996.

Application DetailsApplication code GMF99004Applicant New Zealand Pastoral Agricultural Research Institute Ltd

(AgResearch)Purpose To field test in containment in the Waikato region,

genetically modified sheep with an inactivated myostatin gene, to increase the understanding of myostatin function in order to identify the effects on sheep muscularity

Date application received

16 June 1999

ERMA New Zealand contact

Erika Anderson

DecisionThe application is approved with controls for a period of five years from the date of this decision.

The organism is:

Ovis aries (sheep)

Construct: Plasmid, pBlueScript, containing the sheep myostatin locus (comprising three exons and two introns), a copy of a neomycin (neo) or puromycin (antibiotic resistance) gene originally derived from the bacteria Escherichia coli (E. coli), and a thymidine kinase (tk) gene. Refer to Annex 1 for further details of the genetic construct.

Phenotype: ‘myostatin knockout’ sheep (disruption of the ovine myostatin gene by introduction of the neomycin or puromycin resistance gene into the first exon), resulting in sheep that lack a functional myostatin protein.

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Application ProcessThe application was formally received on 16 June 1999 and verified on 3 December 1999, following a number of additional information requests.

The application was publicly notified on 8 December in The Dominion, The New Zealand Herald, The Press and The Otago Daily Times.

Public submissions closed on 16 February 2000. Eighty submissions were received, of which sixty-four submitters requested to be heard at a public hearing in support of their submission. A list of submitters is attached as Annex 2.

The documents available for the evaluation and review of the application by ERMA New Zealand included: the application and appendices (including supporting documentation and confidential information provided), public submissions, and submissions and comment from other government agencies (including the Ministry of Agriculture and Forestry [MAF], the Department of Conservation [DOC], and the Ministry of Health).

In accordance with section 19(2)(b) of the Hazardous Substances and New Organisms (HSNO) Act 1996, the Authority appointed a Committee to determine the application. The Committee comprised members from the Authority, including: Bill Falconer (Chair), Professor Barry Scott, Dr Oliver Sutherland, Professor Colin Mantell, Dr Lindie Nelson, and one external member, Dr Mere Roberts appointed for her expertise and knowledge in Māori culture and traditions).

HearingA public hearing was held on 6 and 7 April 2000 in Wellington.

Presentations

Presentations were made to the Committee by the following parties:

For the applicant:

1. Michael Holm Partner, Russell McVeagh (Legal Counsel)2. Dr John Bass Programme Leader, Functional Muscle Genomics

(AgResearch)3. Dr Ravi Kambadur Senior Scientist, Functional Muscle Genomics

(AgResearch)4. Jim Napier Research Associate, Functional Muscle Genomics

(AgResearch)

For ERMA New Zealand:

1. Elizabeth Beale Project Leader, ERMA New Zealand

For Ngā Kaihautū Tikanga Taiaoi:

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1. Gerrard Albert Ngā Kaihautū Tikanga Taiao

Submitters:

1. Sue Kedgley Green Party2. Tom Bennion Legal Counsel representing Sue Kedgley and

Associate Professor Peter Wills3. Wendy

McGuinnessPrivate

4. Chris Lester (sheep & Beef Farmer)

Representing Federated Farmers of New Zealand (Inc)

5. Mark Christensen (Anderson Lloyd)

Legal Counsel representing New Zealand Life Sciences Network and Biotenz

6. William Rolleston Representing New Zealand Life Sciences Network and Biotenz

7. Sigi Kirchmair Private8. Kei Munro Private9. Briana Ball On behalf of Berylla Berylla10. Susie Lees Private11. Claire Bleakley Private12. Noel K Wierzbicki Private13. Manfred von

TippelskirchPrivate

14. Tscherner Wolfgang

Private

15. Mary Anne Howard-Clarke

GE Free New Zealand in Food and Environment (RAGE Inc)

16. Bob McDougall Witness to Mary Anne Howard-Clarke [GE Free New Zealand in Food and Environment (RAGE Inc)]

17. Trudy Burgess GE Free NZ18. Alex Vickers Private19. Joanna M Paul Private20. Tracy Buick Private21. Rich J Wernham Private

Further informationAdditional information sought from the applicant and considered by the Committee included:

1 Detailed information in respect of the outdoor containment facility, including both the currently registered 4 ha facility, and the proposed expanded 45 ha facility to enable the Committee to consider and form a view as to the probability of the escape of sheep by theft

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(sabotage) from the containment facilities through negligence, or failure in systems and processes in place.

2 Further detailed information on the electronic subcutaneous microchips proposed to be inserted into genetically modified sheep:

i. the detailed specifications of the proposed microchips

ii. information on their capability to facilitate detection and retrieval of any sheep that may escape from the containment facilities.

3 Further information on animal ethics approvals, including:

i. copies of the full applications and decisions of the Ruakura Animal Ethics Committee (AEC) in respect of work covered under this application

ii. a list of the members, and their respective qualifications, of the Ruakura AEC

Following receipt and consideration of the information specified above, the Committee sought further additional information, including:

i the PGSF Report relating to the funding of the Contract of which the proposed research forms part;

ii further commentary from the Ruakura Animal Ethics Committee on certain aspects of the monitoring of the proposed research.

The information received largely provided further elaboration and detail on material already available, and was not considered by the Committee to constitute new information. In addition sections of this information were provided in confidence to the Committee. However, the following were forwarded to parties to the application:

i Extracts from Section 1 – Parliamentary Section - the PGSF Report (1999-2000)

ii Letter from Applicant to ERMA New Zealand dated 14 August containing information from the Ruakura Animal Ethics Committee

iii Letters from the Chairman of the Ruakura Animal Ethics Committee to the Applicant dated 27 July and 15 August 2000.

Relevant Legislative CriteriaThe application was lodged pursuant to section 40 of the Hazardous Substances and New Organisms Act 1996, and determined in accordance

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with section 45, the additional matters contained in sections 37 and 44, and the matters set out in Part II of the Act.

Consideration of the application followed the relevant provisions of the Hazardous Substances and New Organisms (Methodology) Order 1998 (the Methodology).

The ApplicationThe application is for approval to produce and field test in containment, Ovis aries (sheep) containing a genetic modification aimed at disrupting the ovine myostatin gene locus. The modification involves the introduction of a construct containing an ovine myostatin locus disrupted by the introduction of a neomycin (neo) or puromycin (antibiotic) resistance marker gene. The construct also contains a thymidine kinase (tk) marker gene.

Sheep that are homozygous for the modification are expected to lack the ability to express functional myostatin protein. Myostatin is a protein that is believed to restrict muscle growth and development. The purpose of the work is to increase the understanding of myostatin function in order to identify the effects on sheep muscularity.

This application seeks approval to produce and field test myostatin knockout sheep, from embryos developed under delegated approval. The development of myostatin knockout sheep embryos was approved by the Ruakura Institutional Biological Safety Committee (IBSC) under delegated authority from the Environmental Risk Management Authority (the Authority) on 17 March 1999 (Application code: GMO99/ARR001, ERMA approval code: GMD000056).

The field test will comprise of up to 100 sheep divided into three flocks of approximately 30 genetically modified sheep each.

The genetically modified sheep will be maintained in containment at the Ruakura Research Centre (RRC), in, at various stages, an indoor or outdoor containment facility1.

The indoor facility is a registered containment facility under the Biosecurity Act 1993, in accordance with the Ministry of Agriculture and Forestry (MAF) Biosecurity Authority/ERMA New Zealand Standard Animal Health and Welfare Standard 154.03.03: Containment Standard for Vertebrate Laboratory Animals.

The outdoor facility (45ha site) is registered as a containment facility in accordance with the MAF Biosecurity Authority/ERMA New Zealand Animal

1 A containment facility refers to a place that is registered by MAF under the Biosecurity Act 1993 as a containment facility in accordance with approved standards.

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Health and Welfare Standard 154.03.06: Containment Standard for Field Testing of Farm Animals.

Scope of the applicationThe development of genetically modified embryos has been approved under the HSNO Act 1996 by AgResearch’s Ruakura IBSC under delegated authority from the Environmental Risk Management Authority (the Authority).

The application identifies options for marker sequences that may be utilised in constructs to produce sheep of the phenotype identified. The controls on this approval specify that, any further constructs and genetically modified embryos to be developed, using alternate marker sequences, must be approved by AgResearch Institute’s Ruakura IBSC prior to production and field testing of genetically modified sheep. Schedule 1 to this decision defines the scope of any further constructs to be utilised for the production and field testing of sheep under this approval.

The total number of sheep involved in the field test, including genetically modified and conventional sheep, will not exceed the capacity of the containment facilities, as approved under the MAF Biosecurity Authority/ERMA New Zealand Standards, nor any requirements of the Ruakura AEC, and shall be the minimum number of animals required to obtain statistically significant results.

In essence, this application covers an extension of research already undertaken on the development of the genetically modified sheep embryos. The flock is to be maintained in containment, and there is no intention for the meat, milk or offal from the sheep to enter the human food chain.

Jurisdiction to consider the application as a field test in containment

A submitter questioned whether the application was properly lodged as a “field test in containment” and therefore whether the Committee had jurisdiction to hear it.

The applicant sought approval to field test the sheep to be developed on the advice of ERMA New Zealand, on the basis that the purpose of the research is to increase understanding of myostatin function in order to identify the effects on sheep muscularity, during the life-cycle of the sheep, and under normal conditions ‘in the field’. The applicant might equally have sought approval to develop the sheep as genetically modified organisms. The only practical difference between an application to field test and one to develop is that as regards the latter, the Authority has a discretion whether or not to notify the application, whereas for a field test the Act requires that the application be publicly notified, and

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submissions on it invited. Where the research proposed in an application is strictly neither a development nor a field test (in accordance with the definitions in the HSNO Act 1996), then in advising the applicant, the key consideration for ERMA New Zealand is the nature of the environment in which the research will be undertaken. As the intention is to undertake a portion of the research ‘in the field’, the applicant was advised to make an application to field test in containment rather than to develop the genetically modified sheep. Both the applicant and the Authority accepted this view.

The distinction between a development in containment and a field test in containment is, in this instance, one of presentation rather than substance, and the Authority is of the view that it has the jurisdiction to consider the application as a field test, and that this jurisdiction is not compromised by the fact that the application might also have been considered as a development in containment.

Purpose of the applicationAt the hearing a number of submitters expressed concern at what they perceived to be a change in emphasis with respect to the purpose and potential benefits of the proposed research programme. Specifically, they discerned from the application, that a principal objective behind the stated purpose of increasing understanding of the myostatin function in order to identify the effects on sheep muscularity, was to enable the applicant to identify the scope to develop a variety of heavy muscled sheep in New Zealand for agricultural benefit. In the course of the hearing however, the applicant presented benefits from potential medical applications of the information as being of as equal if not greater importance than these from potential agricultural applications.

Submitters argued that this change in emphasis put them at a disadvantage; some saying that they may not have made submissions at all had they believed the application was aimed at potential medical applications. At the risk of over generalising, the submissions seemed to accept that some account might be taken of potential medical benefits, where these had a high degree of certainty as to their outcome, but did not accept that account should be taken of potential benefits in any other area.

These submissions required the Committee to consider two related issues in relation to applications whose immediate purpose is obtaining scientific information. First, the question of the extent to which the Committee should take into account benefits which may flow from future developments involving that information; and secondly whether the Committee could set any thresholds in relation to the value or benefit of the scientific information being sought.

The issue of how potential future benefits should be weighed by the Authority has been addressed in previous applications. The Committee

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has taken the view to date, that the principal benefit of research programmes such as that involved in the present application is the scientific knowledge they will generate, and that undefined potential future benefits, be they of a medical, agricultural or economic nature, should not be taken into account by the Committee in its assessment of benefits. Any future risks, costs or benefits that may result from the release of an organism, or its commercial use as a food product, or in a pharmaceutical, agricultural or medical context, are more appropriately dealt with in the context of any future applications that may be made for those purposes.

As a general matter, the Committee was of the view that where, as in the present instance, the research programme had been considered and given appropriate funding priority by the applicant, and approved by the Foundation for Research Science and Technology, the Committee might assume, in the absence of evidence to the contrary, that the scientific knowledge to be gained was beneficial in itself, regardless of whatever future benefits may emerge from its use. The sections of the Public Good Science Fund Report to Parliament 1999-2000 relating to the proposed research endorsed its value.

Overall, the Committee concluded, on the basis of the application and the PGSF Report, that information on sheep muscularity would be beneficial in itself, not least because it would likely contribute to a wide range of related research. The Committee did not consider it could more precisely establish immediate benefit thresholds for research of this nature, for example by attaching greater benefit to information which may lead to medical outcomes than that which may lead to agricultural outcomes. Such an approach may encourage applicant’s to misrepresent potential benefits. Nor was the Committee prepared to conclude that this was an area of inquiry which should not be pursued, even though the ultimate applications of the research and the benefits which might flow from it were uncertain.

The Committee accepted that the information could only be obtained efficiently through knockout procedures, noting the applicant’s statement that the heavy muscled sheep variety in New Zealand, Texel, and the European Bextel, are not known to have a mutation for myostatin, and would therefore not be appropriate for this research.

The Committee noted that while one of the research outcomes may be the development of heavy muscled sheep, which might alternatively be pursued through conventional breeding techniques, the applicant’s objective as stated to the PGSF was physiological studies associated with the development of the sheep rather than the sheep themselves. The applicant pointed out that the programme is not looking at muscularity per se, but is determining the function of the myostatin gene using sheep as an animal model.

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The Committee accepted that though different ethical issues may arise (dealt with subsequently in this decision) there were benefits to be gained from research using larger animals such as sheep (in which the applicant has considerable scientific expertise), rather than smaller laboratory animals.

Key IssuesThe Committee’s consideration of the application encompassed those matters relevant to the application, and included:

1. Adequacy of the proposed containment regime, including:

i. the ability of the organism or any heritable material to escape from containment, including:

(a) escape of whole sheep: escape by human intervention, including as a result of:

- sabotage (including theft)- negligence

events of force majeure (including natural disaster)

(b) escape of genetic material by horizontal gene transfer, via: biting arthropods microorganisms

(c) disposal of sheep and other biological material

ii. the ability of the organism to establish a self-sustaining population

iii. the ease of eradication of any population established.

2. risks associated with the organism, including:

i. risks to public health from the consumption of meat, milk or offal derived from genetically modified sheep, in the event that sheep enter the national flock, and subsequently, the food chain, following an escape from containment, including:(a) direct health effects as a result of consumption(b) development of antibiotic resistance as a result of horizontal

gene transfer to gut bacteria(c) unknown outcomes, ie CJD and long-term unanticipated

health effects

ii. risks to New Zealand’s ‘clean green image’, and export relationships and organic farming

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iii. risks to the relationship of Māori and their culture and traditions with their ancestral lands, water, sites, waahi tapu, valued flora and fauna, and other taonga

iv. the maintenance and enhancement of the capacity of people and communities to provide for their own economic, social, and cultural wellbeing and for the reasonably foreseeable needs of future generations

3. Animal welfare and ethical issues.

4. The benefits to be derived from the application.

Adequacy of the Proposed Containment RegimeThe Committee’s consideration of the adequacy of the proposed containment regime, included:

1. the ability of the organism or any heritable material to escape from containment

2. the ability of the organism to establish a self-sustaining population3. the ease of eradication of any population established.

The ability of the organism or any heritable material to escape from containment

In considering the ability of the organism to escape from containment, the Committee considered inter alia, the following matters:

i. escape of whole sheep

ii. escape of genetic material by horizontal gene transfer

iii. disposal of sheep and other biological material

Sheep under this approval will be maintained in two separate containment facilities, initially in an indoor facility (comprising two non-contiguous rooms), and later in an outdoor containment facility, ‘in the field’.

The Committee was satisfied, subject to the controls imposed in this decision, that the containment regime can adequately contain sheep as a part of this field test. The controls require sheep to be produced and maintained in registered containment facilities, constructed, operated and managed in accordance with the MAF Biosecurity Authority/ERMA New Zealand Standard154.03.06: Containment Standard for Field Testing of Farm Animals (outdoor containment facility), and the MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.03: Containment Facilities for Vertebrate Laboratory Animals (indoor containment facility), and to comply with the controls specified in this approval.

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Furthermore, an additional measure has been put in place over and above the requirements of the standards, to further reduce the probability of any escape of sheep from the outdoor containment facility by the installation of a system to electronically monitor the perimeter fencing in order to promptly detect any interference or break in the fence.

The Committee was satisfied that the management and operational procedures in place are sufficient to ensure that the sheep will be maintained in secure containment.

Under this regime, the Committee concludes that the likelihood of an escape from the facilities is very low.

i. Escape of whole sheep

Human Intervention

The outdoor and indoor containment facilities are located within the AgResearch RRC, and will therefore be under constant close supervision.

The outdoor containment facility, originally registered as a 4ha facility, has been expanded and now comprises a 45ha block. The extended facility has been approved by MAF under the relevant MAF Biosecurity Authority/ERMA New Zealand Standard, and the Committee considers that it provides equivalent containment to the previous 4 ha facility. In order to provide additional security for the outdoor facility the applicant has installed further electronic monitoring systems, and access to the facility is restricted to authorised persons through electronic card access. The electronic systems in place are monitored outside of working hours by an external security provider, enabling immediate detection of any breach of the perimeter fences.

For any potential saboteurs to gain access to the outdoor containment facility they would need to breach a number of levels of security. They would need to gain access to the RRC (which is monitored outside of working hours by a security provider on-site), locate the containment facility, gain access to the facility without triggering the security system, and exit without being detected.

The indoor containment facilities are located within an existing animal handling facility building, located within the RRC complex, and the sheep will be housed in individual pens. Access to these facilities is restricted to authorized personnel involved with the trial. Outside of working hours the facility is locked and infra-red detector beams are in place to detect any breach in the outer security fence monitored by an external security provider.

For any potential saboteurs to gain access to the indoor containment facility, they would also need to breach a number of levels of security. They would need to gain access to the RRC, locate the building in which the indoor facility is located, gain access to that building without

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triggering the security system, locate the containment facilities within the building, gain access to the facilities themselves (past infra-red detector beams), and exit without being detected.

Identification measures in place for genetically modified sheep make sheep in this trial readily identifiable, and distinct from other sheep within the RRC. The identification measures include double tagging of all sheep, comprising either two ear tags (different in appearance to those in common use on the surrounding farm) or an ear tag and a sub-cutaneous microchip, or for rams, an ear tag and a permanent fixed radio tracking device capable of allowing remote detection and location of the animal.

The Committee is satisfied that the construction, operation and management of the containment facilities minimises the likelihood of any deliberate action or sabotage resulting in a breach of containment, taking into account the security monitoring in place, fencing and access restrictions and location of the facilities within the RRC.

In addition the Committee is satisfied that the operational and management procedures in place minimise the likelihood of inadvertent release of organisms by personnel managing the trial.

Force Majeure

The Committee is satisfied that the containment regime proposed by the applicant (including compliance with the MAF Biosecurity Authority/ERMA New Zealand standards and the controls in this decision) is adequate to ensure that genetically modified sheep can be contained in the event of an incident of force majeure, such as natural disaster, including earthquake, flood or fire.

The site of the outdoor containment facility has been inspected by MAF and deemed to be a suitable site for the purpose of maintaining genetically modified farm animals, with the aim of ensuring containment.

In a force majeure event the applicant is required to take immediate steps to secure the facility, and retrieve any animals that may have escaped from the facility. The containment standards for registration of facilities require containment manuals that detail procedures that shall be followed in an event of force majeure.

ii. Escape of genetic material via horizontal gene transfer

Submitters have raised a number of concerns, in respect of this and previous applications, with respect to the occurrence and purported consequences of horizontal gene transfer. This includes such issues as:

the spread of foreign genes to unrelated species by ‘infection’ (horizontal gene transfer)

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the potential for transferred material to create new viruses and/or diseases

the potential for transferred material to contribute to the spread of antibiotic resistance.

Potential for the foreign DNA to move within the genome

Concern was expressed by some submitters that the E. coli gene used had an inherent capacity to move within the genome. The Committee notes that this is not the case. A series of experimental steps are needed to introduce this gene into the sheep because it is unable to insert by itself. The antibiotic resistance gene was selected because it can be used as a selectable marker, not because it can insert or move within the genome. The DNA derived from the E. coli bacterium and introduced into the sheep myostatin gene has no inherent capacity to move between species, or to move to other locations within the genome, because it does not have the genetic elements necessary for transferring itself. Genetic elements that confer the ability for independent movement are well characterised and distinctive, and the DNA to be introduced into the sheep myostatin gene does not contain such sequences, nor will such mobility elements be created by the insertion of the antibiotic resistance gene.

Horizontal Gene Transfer

Under certain conditions genetic material may be able to be transferred to other organisms by non-reproductive means. Such examples of exchange of genetic material are called horizontal gene transfer. These can most commonly occur via bacterial matings and viral infections. Antibiotic resistance is transferred when resistance genes are on plasmids and these plasmids are passed to other cells when bacteria mate (‘conjugate’). In the laboratory transfer of DNA to bacteria requires specialised vectors and/or physiological conditions. If host DNA is transferred by viruses this material is usually random pieces of DNA around the site of virus insertion and is not specific to functional genes. The Committee notes that if horizontal gene transfer between microorganisms, plants and animals was widespread and frequent then most individuals would contain within their genomes a large diversity of genes and other pieces of DNA from a large range of other organisms. This is not the case and reflects the fact that horizontal gene transfer is generally restricted.

For the antibiotic resistance gene (or the disrupted sheep myostatin gene) to move to another organism a series of independent steps would be required. For example, for the gene to be acquired and expressed by a bacterium in the gut of the animal the following minimum number of independent steps would be required:

i. resistance to degradation of the gene in the sheep digestive systemii. uptake of a functional copy of the gene by a bacterium

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iii. integration of the gene into the bacterial genome (either into the chromosome or into a plasmid)

iv. expression of the gene.

Similar multiple steps would be required for other potential transfer pathways (such as transfer to biting arthropods, or transfer via faecal material to soil microbes). Based upon published scientific investigations it is very unlikely that any of these steps would occur. Calculating the likelihood of the transfer path being completed requires the multiplication of each of the individual step probabilities. The likelihood of such a transfer is, therefore, very much lower than any of the individual steps, and so the Committee considers that the risk of horizontal gene transfer by these means is negligible. Gut bacteria are continually exposed to cellular and DNA material from their hosts with no evidence that the bacteria take up and incorporate host DNA. DNA transfer between some gut bacteria has been demonstrated, but this involves direct transfer of plasmids between the bacteria.

iii. Disposal of sheep and other biological material

The focus of the controls to which this approval is subject, is the containment of all genetically modified material, either within the containment facility itself or on-site2 within the RRC. Furthermore the controls require that all other biological material be disposed of on-site. Although the risk of the transfer of genetic material by other than reproductive mechanisms is considered to be negligible, this approval requires that all biological material be disposed of on-site.

This approach provides assurance that all sheep used in the field test, and all biological material will be disposed of in an appropriate manner, and that this is able to be verified through the records and registers the applicant is required to maintain.

For a small-scale field test, there are no practical impediments to on-site disposal, and for these reasons controls relating to various components of biological material all require disposal on-site.

In addition, controls require the applicant to engage in on-going consultation with Ngāti Wairere to develop culturally appropriate mechanisms and protocols for disposal of genetically modified sheep and other biological material.

Disposal of sheep

Controls on this decision require that all sheep involved in the field test be disposed of, when no longer required, on-site in accordance with the provisions of the MAF Biosecurity Authority/ERMA New Zealand Standards 154.03.06 or 1.54.03.03 (as specified in control number 1.12). This

2 On-site refers to any place on AgResearch property within the Ruakura Research Centre

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includes genetically modified sheep and foetuses, surrogate ewes that have borne genetically modified lambs, conventional surrogate ewes that have failed to become pregnant following embryo transfer, and non-genetically modified progeny.

For the purposes of publication and verification of any research results, the applicant may retain semen and/or ova from genetically modified sheep following the conclusion of the field test. Any semen or ova retained shall be held in accordance with the provisions of approvals to develop the genetically modified organism (specifically embryos) and the control conditions to which these approvals are subject.

Disposal of milk

The genetic modification introduced into sheep in this field test involves the disruption (knock out) of the ovine myostatin gene locus. The modification involves the introduction of an antibiotic resistance marker gene, and its protein product will be expressed. The genetically modified (‘knocked out’) myostatin gene is under the control of the gene’s normal promoter and so should demonstrate the same pattern and timing of expression as the unmodified myostatin gene. The ovine myostatin protein is believed to be a negative regulator of muscle growth and development, and is expected to be primarily expressed in the muscle tissue and blood of the modified sheep. The antibiotic resistance gene is under the control of a promoter that is active in most or all cells, and so may be expressed in other cells and tissues. Milk derived from genetically modified sheep may, therefore, differ in composition from milk of conventional sheep, and somatic cells carrying the modified (‘knocked out’) gene and marker sequences may also be present in the milk of genetically modified sheep.

Control conditions on this approval specify that all biological material, including waste milk and cream, be disposed of on-site in accordance with the requirements of the MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.06 or 1.54.03.03.

Disposal of wool

The process of shearing sheep may result in some hair follicles or skin tissue being plucked, and therefore shorn wool may contain DNA (including the modified DNA) adhered to a plucked hair follicle.

Therefore, as for other biological products identified above, control conditions on this approval specify that shorn wool, be disposed of on-site in accordance with the requirements of the MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.06 or 1.54.03.03.

The ability of the organism to establish a self-sustaining population and the ease of eradication

Entry into the National Flock

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Taking into account the containment regime it is considered very unlikely that a genetically modified sheep might escape, enter the national flock undetected, and subsequently breeding with conventional sheep in the national flock.

All sheep in this field trial, including conventional surrogate sheep, are required to be double tagged at all times, comprising either, two ear tags (different in appearance to those in common use on the surrounding farm), or an ear tag and a sub-cutaneous microchip. All genetically modified ewes are required to carry both a visible ear tag and, at an appropriate age, a sub-cutaneous microchip. Prior to microchip implantation genetically modified lambs will be double tagged, with two different ear tags, or have a visible tattoo.

Furthermore, in recognition of the fact that in the event of an escape, a ram poses the greatest risk, in terms of potential to interbreed with conventional sheep in surrounding land, all genetically modified rams are required to wear a permanently fixed radio tracking device capable of allowing remote detection and location of the animal.

All sheep will therefore be readily identifiable in the event of an escape from containment.

Controls, to which this approval is subject, require that in event of unintended or accidental release or escape of genetically modified sheep, that the applicant shall recover the escaped sheep. Furthermore, if there has been any possibility of mating occurring, any possible resulting pregnancies will be aborted, and if not successful, the affected sheep shall be slaughtered and disposed of on-site. Alternatively, any potentially affected ewes shall be identified, destroyed, and disposed of in accordance with the provisions specified in the controls.

Establishment of a Feral Flock

Although sheep are domesticated animals, feral sheep populations do exist in New Zealand. As discussed above escape is considered to be unlikely, because of the nature of the containment regime, and an undetected escape is considered to be even more unlikely because of the proposed management regime. RRC is located adjacent to Hamilton City in a well populated area, and therefore should an undetected escape occur it is very unlikely that the sheep reach a suitable habitat to establish a feral flock and remain.

The Committee therefore concluded that in the event of an escape from containment, it is highly likely that sheep would be identified and retrieved. Furthermore, if there were a prospect that escaped sheep had mated, any affected ewes would be able to be destroyed, the cost of which would be borne by the applicant.

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Effects of the OrganismRisk to Public Health

Concerns with respect to public health have been raised on a number of grounds, including:

i. direct effects as a result of consumption of meat, milk, or offal derived from genetically modified sheep

ii. development of antibiotic resistance as a result of horizontal gene transfer to gut bacteria

iii. unknown outcomes, e.g. CJD, and long-term unanticipated health effects.

i. direct effects as a result of consumption of meat, milk or offal derived from genetically modified sheep

The key issue is that of whether human consumption is likely to occur at all. The flock to be produced under this approval is to be maintained in containment, and there is no intention for the meat, offal or milk from genetically modified sheep, or sheep that have given birth to genetically modified lambs, or surrogate ewes that fail to become pregnant, to enter the human food chain.

The myostatin knockout sheep are expected to lack the ability to produce biologically active myostatin protein, although they will be expected to produce the antibiotic resistance protein product. In all cases the meat and milk will contain some modified genetic material, as the transgenes will be present in every cell of the sheep.

As regards the potential harm to human health resulting from human ingestion of meat, offal or milk from myostatin knockout sheep should it occur, the Committee identified two issues. Firstly, the absence of a normal sheep myostatin protein was considered extremely unlikely to present any ill effects if products from myostatin-deficient sheep were consumed. This is based upon the fact that no altered sheep protein is produced. Furthermore myostatin-defective cattle are consumed without any apparent ill effects. The Committee did, however, take account of the fact that the presence of an antibiotic resistance protein product may provide some potential risk of allergenicity if consumed. There are no published reports indicating that the neomycin or puromycin resistance gene products are allergenic to humans.

While the applicant has no intention of producing food products as a result of this field test, if in the future food products were to be developed from myostatin knockout sheep, further approvals from ERMA, and approval from the Australia New Zealand Food Authority (ANZFA), would be required before production of products for release could be undertaken.

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Allergenicity

The neomycin resistance and puromycin resistance gene products do not pose any significant allergenic concerns. In particular the neomycin resistance gene and its product has undergone detailed biosafety evaluation. Human exposure to the protein without discernible effects on the immune system is assumed to be already occurring given the background of neomycin resistance among microorganisms in the environment and human gut.

Most human allergens have a common set of characteristics (eg similarities in amino acid composition, resistance to degradation in the gut) that enables many potentially allergenic compounds to be identified. As the antibiotic resistance genes (both neomycin and puromycin) to be used in this trial already occur in gut microorganisms without any apparent allergenic effects it is not anticipated that there will be an allergenic response to them.

ii. development of antibiotic resistance as a result of horizontal gene transfer to gut bacteria

Submissions raised the prospect of the development of widespread antibiotic resistance as a result of horizontal gene transfer following ingestion of products derived from genetically modified sheep. The concern arises out of the fact that the genetic modification will introduce an antibiotic resistance gene into the sheep genome. Unless removed the gene (and its product) is expected to be present in the meat, milk and offal of the sheep developed using the selection marker. However, expression of this product in some cells or tissues may be variable, very low, or absent due to the fact that gene expression is also influenced by the local chromatin structure (proteins which bind up the DNA in the chromosomes).

As noted above, the likelihood of consumption of products derived from genetically modified sheep is considered to be very low, as is the likelihood of horizontal gene transfer given the complexity of steps required to achieve it.

Even if such transfer of an antibiotic resistance gene to microorganisms, or to epithelial cells, did occur in the gut the Committee considered that, set against an existing high background level of antibiotic resistance (amongst microorganisms within the gut), the incremental consequence of any transfer would be minimal.

However, in the unlikely event that such a transfer did occur, there is the potential for the antibiotic to be inactivated if taken orally at the same time as meat derived from genetically modified sheep or milk was consumed. The enzyme produced by the resistance gene that is responsible for inactivating the antibiotic is however unlikely to be still present in food if it has been cooked/heated. In addition in the case of

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neomycin it is poorly absorbed by mouth and is given orally only in certain circumstances to reduce gut microorganisms eg preoperative bowel preparation, hepatic encephalopathy. Such patients have dietary restrictions and are very unlikely to be eating meat.

Therefore, taking into account the low likelihood of consumption of such products, and the low likelihood of horizontal gene transfer actually occurring, the risk to human health as a result of the development of antibiotic resistance is considered to be negligible.

iii. unknown outcomes, ie CJD and long-term unanticipated health effects

Escherichia coli

The Committee notes that there was concern expressed by submitters regarding the use of a gene derived from the bacterium Escherichia coli, and the potential for it to lead to disease or genetic instability in the sheep. The gene involved is the neomycin antibiotic resistance gene (or, alternatively, the puromycin antibiotic resistance gene), which is used both as a selectable marker for the genetic modification and also as the means for disrupting the sheep myostatin gene.

Some strains of E. coli, notably strain O157:H7, are known to cause acute diarrhea. This pathogenicity is caused by specific toxins produced by these bacterial strains. In the case of O157:H7 these are cytotoxins (called Shiga-like toxins or verotoxins) that are the products of specific genes carried by this strain. The E. coli strain used in the myostatin research is not a pathogenic strain and does not contain the verotoxin or other toxin genes. The antibiotic resistance gene derived from the bacterium and introduced into sheep does not produce a toxin that causes diarrhea or other diseases in humans; its function is to break down a specific antibiotic compound. Products of this breakdown are not known to be toxic or to have other detrimental effects on human health. The Committee therefore, considers that there is a negligible risk for this E. coli gene to cause disease when introduced into sheep.

Creutzfeldt-Jakob Disease (CJD)

Submissions also raised the prospect that water can be a source of infection for CJD, and that DNA could enter water supplies and provide such an opportunity. This issue is not relevant in the context of this application, as none of the sheep will have scrapie or other prion diseases. Prions (which cause scrapie, CJD, etc) are infectious misfolded proteins derived from specific genes in the genome. Prion proteins all appear to share a similar set of amino acids, so that the potential for a protein to exhibit prion-like activity can be readily identified. The genetic modifications introduced in this application do not contain these prion-like elements. Myostatin and the antibiotic resistance genes have not been shown to have any association with susceptibility to these diseases.

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Therefore, the Committee considered that there is negligible risk of the development of prion-like diseases from these modifications.

Risks to New Zealand’s ‘clean green image’, export relationships and organic farmingSubmitters raised the prospect that the presence of genetically modified sheep (including their maintenance in containment) could jeopardise New Zealand’s expanding organic agricultural and horticultural industries, and its ‘clean green image’.

In particular the concern expressed was that this trial, and others like it, may jeopardise New Zealand’s ability to produce certified organic produce, and tarnish our ‘clean, green image’, and that this poses a risk to the capacity of people and communities to provide for their own economic, social and cultural well-being and for the reasonably foreseeable needs of future generations (section 5(b) Hazardous Substances and New Organisms Act 1996).

Although the Committee does not dismiss such concerns, it considers that they are more relevant to a release application (or the release of products) than to an application covering the conduct of research in containment.

The Committee considers that so long as it is satisfied of the adequacy of the containment controls and management regime, the risks are negligible for current and future generations alike.

Animal Welfare and Ethical IssuesA number of issues related to animal welfare were raised at the hearing. The focus of these concerns was primarily that research aimed at the development of sheep in which muscle growth is not controlled by myostatin may result in “uncontrolled” muscle growth with consequent suffering and deformities for lambs and suffering for their mothers as a result of:

(a) birthing difficulties, resulting in turn in a higher than usual proportion of deliveries by caesarean section

(b) physiological effects such as difficulties in walking as a consequence of heavy muscling

(c) unanticipated morphological effects, including intolerable deformities.

The applicant is required to comply with the relevant sections and regulations of the Animal Welfare Act 1999, and the Animal Welfare Advisory Committee (AWAC) and National Animal Ethics Advisory Committee (NAEAC) guidelines administered by MAF.

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The Animal Welfare Act anticipates that animals will be used in research and may experience some suffering in the process. The Act recognises that manipulation of a small number of animals may result in benefits to a wider group of people or animals, to society generally, or to the environment. The Act manages the use of animals in research and provides for the use of the minimum number of animals required to maximise the benefits, whilst minimising the suffering to the animals.

Any organisation using animals in research must maintain a Code of Ethical Conduct (CEC) approved by MAF setting out policies and procedures to be followed by the organisation and its Animal Ethics Committee. Furthermore every project involving the manipulation of animals, including those undertaken in the course of the development and field-testing of genetically modified sheep covered by this application must be approved by an Animal Ethics Committee (AEC). Normally, where approval has been given the Authority should be able to assume that all animal welfare matters of concern to submitters have been considered and addressed in that approval.

In the present instance this was not evident from the original application, and did not become clear until the Committee made further inquiries. From the additional information received, however, it is evident that the Ruakura Animal Ethics Committee was fully seized of the concerns expressed by submitters when it considered the programme, and that the ongoing monitoring required to be exercised over the research in terms of the AEC’s approval is designed to ensure that harm to lambs and their mothers is avoided or minimised.

In particular it is the expectation of the Ruakura AEC that the project will involve an expert supervising large animal veterinarian to monitor the progress of lambs in utero, and take steps to terminate a pregnancy and/or determine a humane end point where suffering to any animal is in prospect. The Committee concluded that this requirement should be made a control condition of its approval.

In addition, other controls to which this approval is subject, require the applicant to report to the Authority on a regular basis from an animal welfare perspective on issues including the number of and reasons for caesarean sections performed for genetically modified lambs; any physiological effects relating to the heavy muscling of genetically modified sheep; and any unanticipated behavioural or morphological effects. Finally, the applicant is required to forward to ERMA New Zealand any reports provided to the relevant Ruakura AEC in respect of this work.

A submitter raised the legal argument that, as the potential for suffering and deformity would have been created at the time the embryos were modified by knocking out the myostatin gene, this would have preceded the point at which the approval of an Animal Ethics Committee is required. The Animal Welfare Act 1999 specifies that ethics approvals are only required in respect of foetuses more than half way through their term.

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Animal ethical issues, it was argued, should have been considered at the time approval was sought to modify the embryo and, if the applicant’s Animal Ethics Committee was not involved at this point because its jurisdiction was not triggered, then consideration should have been given to the issues by the IBSC and explained in its decision.

The majority of the Committee considered that as a practical matter, the Animal Ethics Committee did address all the issues arising in consequence of the embryos having been modified, even though this was in the context of an application for AEC approval to insert the embryo into the sheep, and after the approval to modify the embryo had been given. Nonetheless, there is a jurisdictional gap here, which until addressed by the Government, needs to be handled by the Authority being able to assure submitters that their concerns have been addressed by the relevant Animal Ethics Committee.

BenefitsThe Committee noted that the principal benefit, as with all research, is the scientific information expected to be gained - in this case from the development of genetically modified sheep based on transfers of genetically modified embryos, with the result, if successful, that the sheep will not express biologically active myostatin, and therefore may contribute to an increased understanding of myostatin function and its effects on sheep muscularity.

For the longer term there may be other benefits, but these will only materialise as a consequence of further research and development, and at this point it would be premature to speculate on what those benefits might be.

Indeed, the majority of the Committee acknowledges that the degree of long term benefit to be derived from this research, as with all fundamental research, is difficult to quantify. However, that is not to say that the knowledge accumulated in the research is not beneficial as that information adds to the pool of knowledge from which other benefits flow, and the Authority accepts that exploratory research is an essential prerequisite for scientific progress.

Immediately, and for the purposes of most containment applications therefore, the issue is not so much whether the longer term benefits outlined will be achieved, but whether research leading to those potential benefits is a legitimate and valuable scientific endeavour.

This programme, to produce, and evaluate the muscle physiology and biochemistry of myostatin knockout sheep, has been endorsed for funding by the Foundation for Research, Science and Technology (FRST). The majority of the Committee accepts that given the significance of the agricultural and pastoral industries in New Zealand, its research institutions should be at the leading edge of research into the genetic

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factors which control and regulate muscle structure and function, and of associated biotechnological innovation, including recombinant research, and technologies of nuclear transfer (cloning) and surrogacy.

Risks to the Relationship of Māori and their TaongaThe applicant conducted consultations with Te Kōtuku Whenua, the environmental agency of Ngāti Wairere, the Tainui hapu which claims mana whenua over the land on which the applicant’s research facilities are located; Waikato Raupatu Lands Trust which also has responsibilities for the land in question; Ngā Mana Tōpu O Kirkiriroa, which comprises all senior kaumātua in the region, and is recognised by all the territorial local authorities in the district on treaty matters; and with Hare Puke who is a kaumātua of Ngāti Wairere and kaumātua to the applicant.

It was evident that a diversity of views towards the application exists within the various bodies consulted with some having no major issues with it.

No submissions on the application were made by Ngāti Wairere, but the applicant appended to the application a Memorandum from Te Kōtuku Whenua containing a statement of Ngāti Wairere’s views towards the application and a number of recommendations which may be summarised as follows:

Ngāti Wairere considers that the alteration of the whakapapa of species is culturally inappropriate and inherently against their tikanga, and that the Authority and the applicant have a statutory duty under Te Tiriti O Waitangi to afford protection to whakapapa as a taonga. If the proposed research involves alteration to normal growth patterns and therefore to the whakapapa of the sheep, with potential risks to the wellbeing of the animals involved, Ngāti Wairere are strongly opposed to the research proceeding. The consequences of proceeding include human health risks, metaphysical imbalances and adverse psychological and physical effects, enduring into the future, for both the mana whenua and all associated with the research or proximate to the land on which this is conducted.

If the Committee should nonetheless decide to approve the application then Ngāti Wairere recommends that every effort be taken to ensure that:

offal holes are designed in a culturally suitable manner as to prevent any potential risks on the receiving environment;

an assessment of the potential risks and benefits to the cultural well-being of Ngāti Wairere be undertaken by personnel agreed between Ngāti Wairere and the applicant.

a contingency plan for escape from the containment facility be established including electrification of the inner fence;

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a monitoring programme be established with representatives of Ngāti Wairere, with provisions covering the avoidance, reduction or mitigation of any adverse effects detected in consequence of the monitoring activity;

ongoing consultation with Ngāti Wairere representatives continue throughout the trial.

The Report of Ngā Kaihautū Tikanga Taiao, the Authority’s advisory body on matters relating to sections 6(d) and 8 of the HSNO Act, after reiterating the points made by Te Kōtuku Whenua consultants, commented as follows:

Ngā Kaihautū takes into account the need to be mindful of its previous decisions. It takes the view that unless there is compelling evidence to the contrary, it should maintain a position that is not clearly inconsistent with these. This view is reinforced by the knowledge of an impending Royal Commission and ERMA New Zealand’s own Generic Issues research project. Until these have provided both ERMA New Zealand and Ngā Kaihautū with a more informed understanding of the issues of concern to Māori, we will maintain our support for the precautionary approach as it pertains to both science and ethics concerning this type of research, particularly in organisms intended for eventual field release and/or possible human consumption.

In view of the above considerations, Ngā Kaihautū Tikanga Taiao recommends that the Committee decline this application.

Similar issues to those raised by Te Kōtuku Whenua and Ngā Kaihautū arose in the application considered by the Authority (GMF98009) to field test cattle developed from embryos into which had been inserted a copy of gene coding for the human protein myelin. That case was regarded more seriously by Ngāti Wairere in that it involved the transplantation of a gene coding for human protein, whereas the present application involves the knockout of a gene – although in both cases the point at issue is the intereference with the whakapapa of the manipulated species. And in the present instance, the recommendations made by Ngāti Wairere, through the applicant, contemplate the possibility of the Committee approving the application.

The Committee acknowledges the seriousness of the matters raised by Te Kōtuku Whenua on behalf of Ngāti Wairere and has weighed them carefully. As with the cattle decision however, the majority of the Committee did not consider that these matters were such as to justify declining the application. In so concluding, the majority noted in particular that there was a diversity of views towards the application amongst those consulted by the applicant.

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Most of the matters contained in the recommendations of Ngāti Wairere regarding the disposal of offal, containment, monitoring and consultation have been addressed in the controls attaching to this decision.

As regards the health risk assessment sought by Te Kōtuku Whenua, the majority of the Committee does not believe it is practical to require that this be undertaken as a condition of the approval, but it is of the view that if Ngāti Wairere choose to undertake the assessment themselves, the applicant might look for ways of providing practical support.

Overall evaluation of risks, costs and benefits and conclusionsPursuant to section 45(1)(a)(i) of the Act, the Committee is satisfied that this application is for one of the purposes specified in section 39(1) of the Act, being section 39(1)(b): Field testing any new organism.

The Committee is satisfied that the proposed containment regime, together with the additional controls imposed by the Committee, will adequately contain the genetically modified sheep and any heritable material. The likelihood of escape from the facilities is very unlikely, and the likelihood of any escape going undetected with consequent failure to retrieve the escaped animals and take action to manage any possible matings that have occurred, is considered to be even more unlikely. In recognition that rams pose the greatest risk in the event of escape from containment, the controls require all genetically modified rams to wear a permanently fixed radio tracking device allowing remote detection and location of the animal.

The Committee concludes that risks to the environment and human health from the possible escape of the genetically modified sheep are negligible, given the nature and extent of the containment and sheep management regime set out in this approval.

The Committee gave particular consideration to animal welfare issues. The Committee notes the jurisdictional gap that exists in the Animal Welfare Act 1999 in relation to foetuses that are less than half way through their term. Nevertheless the Committee is satisfied that the Ruakura Animal Ethics Committee has considered all the issues that arise in consequence of the embryos being modified. Controls on this application ensure that the husbandry of the animals shall be overseen by an experienced large animal veterinarian who has authority to terminate the pregnancies or the trial, should it be necessary to avoid unacceptable suffering.

The majority of the Committee concludes that the proposed research for which this field trial application is sought, is a legitimate and valuable scientific endeavour. Research results may contribute to an increased understanding of myostatin function and its effects in sheep muscularity, and contribute to a wide range of related research. The majority of the

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Committee accepts that the information can only be obtained efficiently from knockout procedures, noting that heavy muscled sheep such as Texels and Bextels are not known to have defective myostatin, and would therefore not be appropriate for this research. Further, given the significance of agricultural and pastoral industries in New Zealand, its research institutions should be at the leading edge of research into genetic factors that control and regulate muscle structure and function, and of associated biotechnology techniques. The majority of the Committee also accepts that there are scientific benefits to be gained from research using larger animals such as sheep (in which the applicant has considerable experience), in addition to smaller laboratory animals.

The Committee acknowledges the seriousness of the matters raised by Te Kōtuku Whenua on behalf of Ngāti Wairere and has weighed them carefully. The Majority of the Committee did not consider that these matters were such as to justify declining the application. In so concluding, the majority noted in particular that although it have given particular attention to the views expressed by Ngāti Wairere through the Te Kōtuku Whenua there was a diversity of views towards the application amongst those consulted by the applicant. Most of the matters contained in the recommendations of Ngāti Wairere regarding the disposal of offal, containment, monitoring and consultation have been addressed in the controls attaching to this decision.

Minority DecisionThe minority considers that the application should be declined on three grounds:

First, because of the adverse effects it may have on Ngāti Wairere, approval of this application imposes yet another affront to these people already burdened by concerns about a previous application. The cumulative effect is likely to contribute to increased stress on their spiritual and physical well being.

Secondly, on the grounds that the consultation process did not provide a sufficiently robust basis on which to properly evaluate and weigh the risks, effects and benefits to tangata whenua. The minority argues that a process in which the applicants themselves conduct the assessment of cultural effects is inappropriate and seriously flawed. Instead it is suggested that assessment of cultural effects should in future be conducted or facilitated by an independent and appropriately qualified person or persons - a situation which is likely to engender more trust and willingness by iwi to engage in a fully informed way in the process. An additional problem was the conflation of this application with a previous one (GMF98009) a situation which, by their own admission, led tangata whenua to give inadequate time and attention to this particular proposal. Of concern also was the potential for conflict of interest among the source of advice sought by the applicant on cultural risks and effects.

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Thirdly, because the proposed benefits of the scientific information to be obtained from this research do not outweigh the possible adverse effects on the health and well being of the animals involved in the programme. The minority believes, as a general principle, that approval should only be given if the outcomes are clearly perceived to be of benefit to society, and/or where there are considered to be no viable alternatives to the research.

The application for the field testing of myostatin knockout sheep is thus approved with controls.

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Controls

In order to provide for the matters detailed in Part I of the Third Schedule to the Act, Containment Controls for Development and Field Testing of Genetically Modified Organisms, the approved organisms are subject to the following controls:

1. To limit the likelihood of any accidental release of any organism or any viable genetic material3:

1.1 The applicant before field testing sheep containing any construct not yet developed, shall obtain development approval, under the Hazardous Substances and New Organisms Act 1996, from the AgResearch Institute’s Ruakura Institutional Biological Safety Committee (IBSC) and provide a declaration in writing to the Authority verifying that:

1.1.1 the construct and genetically modified embryo has been developed in accordance with an approval under section 39(1)(a) of the Act

1.1.2 the construct and genetically modified embryo complies with the requirements detailed in the attached schedule to this decision

1.1.3 the genetically modified cell line (nuclear donor) from which the embryo is produced contains the transgene (verified by methods including, but not limited to, the Polymerase Chain Reaction (PCR) or Southern hybridisation analysis).

1.2 The operation, management and construction of the indoor containment facilities4 shall be in accordance with the Ministry of Agriculture and Forestry (MAF) Biosecurity Authority/ERMA New Zealand Standard 154.03.03: Containment Facilities for Vertebrate Laboratory Animals.

1.3 The indoor facility shall be approved by MAF as a containment facility in accordance with the MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.03 prior to housing of any sheep under this approval.

3 Viable Genetic Material is biological material that can be resuscitated to grow into tissues or organisms. It can be defined to mean biological material capable of growth even though resuscitation procedures may be required, eg when organisms or parts thereof are sublethally damaged by being frozen, dried, heated, or affected by chemical.4 Containment facility means a place approved in accordance with section 39 for holding organisms that should not, whether for the time being or ever, become established in New Zealand. Biosecurity Act 1993

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1.4 The operation, management and construction of the outdoor containment facility shall be in accordance with the MAF Biosecurity Authority/ERMA New Zealand Animal Health and Welfare Standard 154.03.06: Containment Standard for Field Testing of Farm Animals.

1.5 The outdoor facility shall be approved by MAF as a containment facility in accordance with the MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.06 prior to the introduction of any sheep into the facility.

1.6 The production and maintenance of genetically modified sheep in the containment facilities shall be in accordance with the relevant sections and regulations of the Animal Welfare Act 1999, the Animal Welfare Advisory Committee (AWAC) and National Animal Ethics Advisory Committee (NAEAC) guidelines administered by MAF, and the local AgResearch Institute’s Animal Ethics Committee (AEC). The husbandry of these animals shall be overseen by an experienced large animal veterinarian, who shall have the power to determine a humane endpoint for any part of the trial or overall endpoint of the trial.

1.7 The maximum number of sheep in the field test shall not exceed the capacity of the containment facilities, and/or any requirements of the relevant Animal Ethics Committee, and should at all times be the minimum number of animals required to obtain statistically significant results.

1.8 The maximum number of genetically modified sheep in the field test shall not at any one time exceed 100 animals.

1.9 The identification system for genetically modified sheep shall enable information on the genotype and generation (T0, T1 etc) to be derived from a database maintained by the applicant.

1.10The outdoor containment facility shall be enclosed by a double perimeter fence constructed in accordance with the requirements specified in the MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.06. The inner perimeter fence shall be electronically monitored and alarmed (in order that the location of any breach of containment is detected immediately), stock-proof and capable of preventing entry and escape of sheep.

1.11No genetically modified sheep shall leave the containment facilities except in accordance with the MAF Biosecurity Authority/ERMA New Zealand Standards, as described in controls 1.2 and 1.4.

1.12 In the event that operations involving genetically modified sheep cease, all genetically modified sheep in the containment facilities shall be destroyed and disposed of on-site in accordance with the requirements of the MAF Biosecurity Authority/ERMA New Zealand

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Standard 154.03.06, and of any requirements under the Resource Management Act 1967, and in consultation with Ngāti Wairere with respect to developing culturally appropriate mechanisms and protocols for disposal.

1.13All sheep no longer required for breeding and any biological material (including semen, ova, milk and shorn wool) derived from genetically modified sheep no longer required for the purpose of this application shall be disposed of on-site5 in accordance with the requirements of the MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.06, and of any requirements under the Resource Management Act 1967, and in consultation with Ngāti Wairere with respect to developing culturally appropriate mechanisms and protocols for disposal. Ova and semen can be kept in secure containment for record purposes.

1.14The applicant shall provide ERMA New Zealand and the facility Supervisor6 (MAF) with a timetable for the production and field testing of genetically modified sheep approved under this decision, and shall notify ERMA New Zealand and the facility Supervisor, in writing, of any changes to that timetable.

1.15At all times only persons authorised by the Operator or the Manager of the containment facilities shall have access to the containment facilities, other than those identified in control 6.1

1.16All sheep in the field test (whilst in the indoor and outdoor containment facilities) shall be double tagged at all times.

1.16.1 All genetically modified ewes shall be individually identified by an ear tag for visible identification and also implanted with a subcutaneous electronic microchip for individual electronic identification. In the event that subcutaneous microchips cannot be inserted until sheep reach a certain age, sheep should have two different types of ear tag in place at all times, allowing for immediate identification.

1.16.2 All genetically modified rams shall be fitted with a permanently fixed radio tracking device capable of allowing remote detection of the location of rams at all times.

2. To exclude unauthorised people from the facility:

2.1 The applicant shall comply with the requirements contained in the standards listed in control 1.2 and 1.4 relating to identification of

5 On-site refers to any place on AgResearch property within the Ruakura Research Centre.6 An Inspector appointed under the Biosecurity Act.

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entrances, numbers of and access to entrances, and security requirements for the entrances and the facility.

3. To exclude other organisms from the facility and to control undesirable and unwanted organisms within the facility:

3.1 The applicant shall comply with the requirements contained in the standards listed in control 1.2 and 1.4 relating to exclusion of other organisms from the facilities and the control of undesirable and unwanted organisms within the facilities.

3.2 In the event of mortality in genetically modified sheep in the field test site, carcasses shall be immediately removed to prevent access to scavengers and following investigation as required by Section 4.8 of The MAF Biosecurity Authority/ERMA New Zealand Standard 154.03.06, the carcasses shall be disposed of on-site in accordance with the provisions specified in control 1.12.

4. To prevent unintended release of the organism by experimenters working with the organism:

4.1 The applicants shall comply with the requirements contained in the standards listed in control 1.2 and 1.4 relating to the prevention of unintended release of the organism by experimenters working with the organism.

4.2 No part or product of the transgenic organism shall be ingested by any person at any time.

5. To control the effects of any accidental release or escape of an organism:

5.1 In case of unintended or accidental release or escape of genetically modified sheep involved in the field test, the applicant shall recover the escaped sheep to the containment facility. If there has been any possibility of mating occurring, steps shall be taken to abort any possible resulting pregnancies. If the abortion is not successful, the affected sheep shall be slaughtered and disposed of on-site. Alternatively, any potentially affected ewes shall be identified and destroyed, and be disposed of in accordance with the provisions specified in control 1.12.

5.2 If for any reason a breach of containment occurs the applicant shall notify the facility Supervisor (MAF) and ERMA New Zealand immediately the event is noticed (and at least within 24 hours of the breach being detected).

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6. Inspection and monitoring requirements for containment facilities:

6.1 The Authority or its authorised agent or properly authorised enforcement officers, or supervisor under the Biosecurity Act 1993, may inspect the containment facility at any reasonable time.

6.2 The applicant shall provide a comprehensive report to ERMA New Zealand in each December on the progress in the production and field testing of genetically modified sheep, including an inventory (a register that records the identity and fate of all sheep in the field trial), with particular reference to the topics listed in section 4.13 of the MAF Biosecurity Authority/ERMA Standard 154.03.06. This report shall also include:6.2.1 information on animal welfare issues including; unexpected

birthing difficulties, unexpected mortalities and any unusual physiological, morphological, and behavioural effects resulting from the genetic modification;

6.2.2 information on the stability of the genetic constructs used in genetically modified sheep; and

6.2.3 any reports provided to the local Ruakura Animal Ethics Committee7.

6.3 The applicant shall provide a final report to ERMA New Zealand at the conclusion of the approval period, being five years from the date of this decision. This shall include:6.4.1 information on the items listed in section 4.13 of the MAF

Biosecurity Authority/ERMA Standard 154.03.066.4.2 information on animal welfare issues including; unexpected

birthing difficulties, unexpected mortalities and any physiological, morphological and behavioural effects resulting from the genetic modification

6.4.3 information on the stability of the genetic constructs used in genetically modified sheep

6.4.4 any reports provided to the local Ruakura Animal Ethics Committee.

6.4 The applicant shall establish an on-going liaison committee with Ngāti Wairere, to enable Ngāti Wairere to monitor the implementation and progress of the field test, and to provide a forum for the exchange of information on the science of genetic modification.

7 Animal Ethics Committee

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7. Qualifications required of the persons responsible for implementing those controls:

7.1 The applicant shall comply with the requirements of the standards listed in control 1.2 relating to the training of personnel working in the facility.

7.2 The applicant shall notify the Supervisor and ERMA New Zealand if there are any changes in ownership of property housing the containment facility maintaining organisms under this approval.

______________________ ___________________Chair Date

______________________Name

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ReferencesFuchs RL, Ream JE, Hammond BG, Naylor MW, et al. Safety assessment of the neomycin phosphotransferase II (NPTII) protein. Bio/technology 1993; 11: 1543-47.

Huby, R.D., Dearman, R.J., Kimber, I. (2000). Why are some proteins allergens? Toxicol. Sci. 55, 235-246.

Karenlampi S. Health effects of marker genes in genetically engineered food plants. Copenhagen: Nordic Council of Ministers, 1996.

Mackenzie D. Gut reaction. Could a mechanical gourmet help us digest a GM future? New Scientist. 30 January 1999: p4

Metcalfe DD, Astwood JD, Townsend R, Sampson HA, et al. Assessment of the allergenic potential of foods derived from genetically engineered crop plants. Crit Rev Food Sci Nutr 1996; 36(S): S165-86.

US Food and Drug Administration. Guidance for industry: use of antibiotic resistance marker genes in transgenic plants. Draft. Rockville: US FDA, September 1998.

US Registry of Toxic Effects of Chemical Substances

1997. Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc. Natl. Acad. Sci. USA 94, 961-966

1999, Immunization via hair follicles by topical application of naked DNA to normal skin. Nature Biotechnology 17 (870-872)

World Health Organization. Biotechnology and food safety: report of a joint FAO/WHO expert consultation. Geneva: World Health Organization, 1996

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Schedule 1Organism: Sheep (Ovis aries)

Construct: Myostatin knockout (disruption of the sheep myostatin locus by the introduction of a neomycin or puromycin (antibiotic) resistance gene.

Genetic modifications: The constructs shall contain only genes, promoters and marker sequences specified in the application.

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Annex 1Details of the genetic modificationGene Construct

The sheep myostatin locus with three exons and two introns has been cloned into pBlueScript. The neomycin or puromycin resistance gene has been cloned into the 1st exon of myostatin. This will enable the selection of homologous recombination events by resistance to G418 (Geneticin). The diagram below illustrates the unmodified and modified myostatin gene.

The figure shows the genomic structure (panel A) and the knockout construct (panel B). The myostatin gene contains three exons and two introns. The exons are denoted in light shading, and the introns in dark shading. The nucleotide numbers corresponding to the exons are shown. In the knockout construct the neomycin (neo) gene is inserted between nucleotides 330 and 331 of the 1st exon, and the thymidine kinase (tk) gene is cloned at the 3’ end of the myostatin gene. The knockout construct is generated using pBlueScript (SK+). While the neomycin resistance gene is used for positive selection of homologous recombinations at the myostatin locus, the tk gene will be used as a negative selection marker for non-specific integration.

Source of Nucleic Acid

The sheep myostatin locus has been PCR-amplified using genomic DNA from “Thomas” (Cloned sheep) as a template. The neomycin8 and puromycin9 resistance genes used in this project are synthetic sequences identical to those located in the E. coli genome.

8 Southern PJ and Berg P. 1982 Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. Journal of Molecular and Applied Genetics, 1 327 – 341.

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= EXON

= INTRON

Myostatin Knock out construct

Myostatin Genomic structure

1 373 1128374 740 741

neo tk374 740 741-126 +330 331 1128

A

B

List of submittersAnnex 2

9 De la Luna S, Soria I, Pulido D, Ortin J and Jiminez A. 1988 Efficient transformation of mammalian cells with constructs containing a puromycin-resistance marker. Gene 62(1) 121 – 126.

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No.

Name Organisation Position Address Request to be heard

1 Susan Redward Federated Farmers of New Zealand (Inc)

Policy Manager PO Box 715 WELLINGTON Yes

2 Berylla Berylla 24 Montcalm Street NELSON Yes3 Duncan Sloss 12 Newbury St Opawa CHRISTCHURCH Yes4 Robert Anderson 440a Otumoetai Road TAURANGA No5 Tim Vallings Brit Rd RD 8 WHANGAREI Yes6 Zelka Grammer Bint Road R D 8 Maungakaramea

WHANGAREIYes

7 Susie Lees 14 Hastings Street NELSON Yes8 Justine Gresson 50 Sheldon St CHRISTCHURCH Yes9 Paul de Spa 50 Sheldon St CHRISTCHURCH Yes

10 Norman Fletcher PO Box 17 Waikawa Bay PICTON Yes11 Wendy McGuinness 50 Cashmere Avenue Khandallah WELLINGTON Yes12 Tscherner Wolfgang 326 Princess Drive NELSON Yes13 Pip Direen 50 Atkins St MOTEUKA Yes14 Gina Luke 4 Landy St Dallington CHRISTCHURCH Yes15 Genevieve Claire de

Spa 125 Kainga Rd CHRISTCHURCH 4 No

16 Claire Bleakley Pigeon Bush Western Lake Rd FEATHERSTON Yes17 Associate Professor

Peter Wills Department of Physics The University of

AucklandPrivate Bag 92 019AUCKLAND

Yes

18 V A Clayton c/- Ginny's Herbs PO Box 35 MaungakarameaNORTHLAND

No

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No.


19 Carolyn Rhodes 32 Wembley St CHRISTCHURCH 8002

Yes

20 Mike Drake PO Box 10 Tapawera NELSON Yes21 Budyong & Lesley

Hill 11 Huiawa St WAIKANAE 6454 No

22 Alan J Baldwin 94 Marne St PALMERSTON NORTH

No

23 Mike Aitkenhead PPL Therapeutics (New Zealand) Ltd

RD 1 Mangakino No

24 Gilbert Urquhart 48 Glenroy St CHRISTCHURCH Yes25 Dr Rebecca Potts 33 Wyndham St AUCKLAND Yes26 Malcolm Frost 107 Havelock Road Havelock North HAWKES BAY Yes27 Elizabeth Frost 107 Havelock Road Havelock North HAWKES BAY Yes28 Rich J Wernham 54 Eden St Island Bay WELLINGTON Yes29 Mary Anne Howard-

ClarkeR.A.G.E Inc National

SpokespersonPO Box 30 762 LOWER HUTT Yes

30 Helen Scott 185A Keyes Rd New Brighton CHRISTCHURCH Yes31 Manfred von

Tippelskirch 185A Keyes Rd New Brighton CHRISTCHURCH Yes

32 Pat Lee 54 Waipori St Berhampore WELLINGTON No33 Don and Rose Craig Green Horizons

Organics Ltd PO Box 113 Kirwee CHRISTCHURCH Yes

34 Marcus Graf 24 Baildon Rd Grey Lynn AUCKLAND Yes35 Shannon McGhee Pupuke Rd RD 2 Kaeo 0471

NORTHLANDYes

36 Jon Muller Member for R.A.G.E Inc

PO Box 39 158 WELLINGTON Yes

37 Sam Stocker 54 Waipori St Newtown WELLINGTON No38 Jim Gladwin 22a Walsall St Avondale AUCKLAND Yes

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No.


39 Tammy Meaglter 50 Atkins St MOTUEKA Yes40 Sara Tree 35 14th Avenue TAURANGA Yes41 Ngaire Irwin 77 Owairaka Ave Mt Albert AUCKLAND Yes42 Kelly Newman PO Box 54 NELSON Yes43 Tahu Erlbeck PO Box 54 NELSON Yes44 John Janke Hamama Rd RD 1 TAKAKA Yes45 H J Clark 20 Bishopdale Ave NELSON Yes46 Joanna M Paul 3 Maxwell Ave WANGANUI Yes47 Oraina Jones 47 Ellis St Brightwater NELSON Yes48 Sue Kedgley MP Parliament Buildings WELLINGTON Yes49 Sigi Kirchmair 9 Leach Place NELSON Yes50 Alison Fletcher PO Box 17 Waikawa Bay PICTON Yes51 Graeme North and

Deniece Gannaway Matthew Road RD 1 WARKWORTH Yes

52 Alex Vickers Flat 1 44 Roxburgh St Mt VictoriaWELLINGTON

Yes

53 New Zealand Life Sciences Network

c/- Mr MRG Christensen

Anderson Lloyd Level 13, Forsyth Barr House

Cnr Armagh & Colombo StCHRISTCHURCH

Yes

54 Biotenz C/- Mr MRG Christensen

Anderson Lloyd Level 13, Forsyth Barr House

Cnr Armagh & Colombo StCHRISTCHURCH

Yes

55 Raymond Vogt 89 Maungaraki Rd Petone WELLINGTON Yes56 Julia Bromley 177 Vanguard St NELSON Yes57 Tejas Arn 177 Vanguard St NELSON Yes58 Estelle Courtney 1 Boyes Place NELSON Yes59 Marcia Higgs c/- 11 Dundas St NELSON Yes60 Nick Young 57 Wolfe St NELSON Yes

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No.


61 Kei Munro 385 Brook St NELSON Yes62 Nicholas Owen 276 Hardy St NELSON Yes63 Joanne Emery 94 Collingwood St NELSON Yes64 Diana Kirpensteijn 5 Ombersley Tce CHRISTCHURCH No65 Zanna Bird 64 Brougham St NELSON Yes66 Andrea Chandler 33 Queens Rd NELSON Yes67 Grant Scott 128 Grove St NELSON No68 Paul Brumwell East Takaka Rd Takaka GOLDEN BAY Yes69 Charles

Satterthwaite 35 Van Asch St Sumner CHRISTCHURCH No

70 Peter and Kerry Green

PO Box 133 TAKAKA No

71 Tracy Buick 68A Taupo St Green Bay AUCKLAND Yes72 Jeff and Karen Hay PO Box 62 TAKAKA Yes73 Silvia Gassebner 9 Leach Place NELSON Yes74 Bruce Dyer PO Box 984 NELSON No75 Michael Glover Waihora Days Bay RD 4

CHRISTCHURCHYes

76 Trudy Burgess GE Free NZ National Coordinator

PO Box 693 NELSON Yes

77 Jim Chapple 260 Willoughby Rd RD 1 KATIKATI No78 Penelope Buxton 192 Clyde Rd Fendalton CHRISTCHURCH No79 Peter Davis 11 Aorangi Tce WELLINGTON No80 Noel Wierzbicki RD 9 PALMERSTON

NORTH Yes

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Annex 3

Qualitative scales for describing effects

Adverse effectsQualitative assessments use words to describe the probability or likelihood of the adverse effect occurring and the magnitude, or a measure of the severity of that adverse effect. These are combined to form a qualitative estimate of the level of risk. The following sets of word scales are used:

Table 1: Likelihood of effect

Descriptor DescriptionVery unlikely Not impossible, but only occurring in exceptional

circumstances

Unlikely Could occur, but is not expected to occur under normal conditions

Possible 50:50 chance of occurring, or where there is insufficient information to judge likelihood otherwise

Likely Will probably occur at some time

Very likely (almost certain)

Is expected to occur

Table 2: Magnitude of adverse effect

Descriptor Examples of descriptionsMinimal Insignificant (repairable or reversible) environmental

impact, no observable cultural effects, other effects slight (reversible) or very small

Minor Reversible environmental impact, limited adverse cultural effects (affecting small area or localised community), other effects small and limited in scope

Moderate Some slight effect on native species, adverse cultural effects to wider area but not considered serious, other effects medium or mid range

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Major Irreversible environmental effects but no species loss, adverse cultural effects widespread but remedial action available, other effects large

Massive Extensive irreversible environmental effects, including species loss, adverse health effects, severe adverse cultural effects over whole country with no possible remedial action, other effects very large and widespread

Beneficial effects

The word scale used to describe the likelihood of beneficial effects is the same as stated in Table 1 above. A qualitative assessment to describe the magnitude of beneficial effects has been made. The following word scale is used:

Table 3: Magnitude of beneficial effect

Descriptor Qualitative descriptionMinimal Very small or insignificant benefit

Minor Small benefits that are localised in distribution

Moderate Medium benefits that are localised in distribution

Major Large benefits that are regional level in distribution

Massive Very large benefits that are national in distribution

i Ngā Kaihautū Tikanga Taiao has been formally established under clause 42 of the First Schedule to the Hazardous Substances and New Organisms Act 1996, as a Māori advisory committee, to advise the Authority on how to take account of issues of concern to Māori (particularly in relation to sections 6(d) and 8 of the Act).

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