Scientific Advisory Committee on Genetic Modification (Contained Use): Annual Report January to December 2007

Table of Contents

Foreword

It gives me great pleasure to present the Annual Report 2007 of the Scientific Advisory Committee on Genetic Modification (Contained Use) (SACGM(CU)).

It has been a busy year for the Committee, delivering advice on technical issues relating to risk assessments covering an increasingly diverse body of research. As the underpinning science become more complex, we share expertise with other relevant scientific committees and the secretariat and members of ACRE (Advisory Committee on Releases to the Environment) have been present at our meetings.

In addition to the mainstream committee work, members have been very active as we have several discrete, specialist working groups to re-write the esteemed ACGM Compendium of Guidance to incorporate the latest technological and regulatory developments. After a lot of hard work and contributions from our stakeholders, the SACGM(CU) Compendium of Guidance was launched at our second public meeting earlier in the year.

The Committee is committed to openness, and our agendas and minutes are published on our website with discussion papers available upon request.

I should like to take this opportunity to thank my fellow committee members for their invaluable expertise and impartial contributions to our deliberations. Without this, we would not be able to operate effectively. Their time commitment is valued greatly.

Last but by no means least, I express my gratitude to the hard work and expertise of our Secretariat and send kind regards those staff who have moved to new roles in HSE during this year.

Professor Janet Bainbridge, OBE

July 2008

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Introduction

Established in 2004 in accordance with the Office of Science and Technology’s Code of Practice for Scientific Advisory Committees (CoPSAC), the SACGM(CU) (hereafter referred to as the Committee) is a non-statutory scientific advisory committee. The Committee provides scientific advice to the UK Competent Authority (CA) on the contained use of genetically modified organisms, particularly in respect of hazard identification and risk assessment.

The Health and Safety Executive (HSE) provides the Secretariat for the Committee. The Secretariat liaises closely with the Chair, other members of the CA and prepares papers, organises and hosts the Committee’s meetings.  The Secretariat also prepares reports from the Committee and draft guidance arising from advice of the Committee. The Secretariat also maintains the SACGM(CU) website, where information about the Committee, its members, as well as meeting agendas and minutes may be downloaded.

In 2007, the Committee held three main meetings:

• 1 February 2007 – 10th meeting (2nd Open Meeting)
• 28 June 2007 – 11th meeting
• 28 November 2007 – 12th meeting

In addition to these meetings, a number of meetings of the various Compendium of Guidance Working Groups were held to finalize their respective sections of the Compendium of Guidance.

The Compendium of Guidance represents what the Committee considers to be safe and good practice when working with genetically modified organisms (GMOs) in a contained use setting. Whilst it is not mandatory to follow this guidance, doing so will almost certainly ensure that workers are complying with the health and safety law that governs laboratory work with GMOs. The guidance is widely used by the research community.

Terms of Reference

SACGM(CU) provides scientific and technical advice to the UK CA on the risks posed to human health and to the environment from the contained use of genetically modified organisms. In particular the Committee:

• provides advice on the technical issues of individual activities notified under the Genetically Modified Organisms (Contained Use) Regulations 2000 (as amended in 2005) – (GMO(CU));
• provides advice on risk assessments for contained use activities involving GMOs; and
• develops and updates guidance on all aspects of contained use of GMOs including the SACGM Compendium of Guidance.

UK Competent Authorities for Genetic Modification (Contained Use) Activities

The Health and Safety Executive and the Secretary of State for the Department for Environment, Food and Rural Affairs (Defra) form the Competent Authority in England and Wales. In practice, these functions are delegated to HSE and Defra officials. In Scotland, the Competent Authority comprises the Scottish Ministers and HSE and similarly these functions are delegated to officials of HSE and the Scottish Government. Although not part of the Competent Authority, the National Assemblies for Wales and Northern Ireland are included in all UK CA considerations.

The roles and responsibilities of the different members of the UK CA are set out in Appendix 1.

Genetically Modified Organisms

Genetic engineering is different from traditional breeding methods in that the organism’s genes are manipulated directly. A multicellular organism that has been modified in this way is referred to as a genetically modified organism (GMO). Similarly, modified micro-organisms are referred to as GMMs (genetically modified micro-organisms).

Contained use (CU) is where control measures are used to limit contact between GMOs, humans and the environment. In practice, this involves work in laboratories, animal houses, indoor plant growth facilities and large-scale production facilities on industrial sites. The vast majority of GM work includes strategies that severely incapacitate the organism so that it is unable to survive or proliferate outside of the laboratory without specified ‘artificial’ growth requirements. For the smaller number of activities involving organisms still capable of growth outside of the laboratory, a robust risk assessment must be submitted for scrutiny by the CA with identified appropriate and proportionate containment measures to prevent release, before work may commence. The safety record in this sector is therefore extremely good.

During 2007, a total of 180 notified GM activities were received by the CA. In addition to these listed consent for four Class 4 activities was withdrawn:

Class of Activity	Number Received
1 (New premises)	29
2	121
3	18
4	0
Significant change to work	8
Accident	4

Details of all GM work notified to HSE may be found on the electronic GM Public Register. The majority of notified activities involved the use of replication defective viral vectors (either adenovirus or retrovirus based systems) for expression of transgenes in mammalian cells.

Membership

The Committee has expertise/representation in the following areas:

• Molecular virology
• Molecular bacteriology
• Clinical applications (i.e. gene therapy, vaccine development, clinical virology, molecular oncology)
• Molecular plant biology
• Environmental microbiology
• Biological safety
• Non-Governmental Organisation (NGO)
• Trades Union Representative

The Committee comprises a Chair, Vice Chair and 14 members as follows:

• Professor Janet Bainbridge, OBE (Chair)
• Professor Martin Gore (Vice Chair), Royal Marsden Hospital, London
• Dr Gary Burns, MBE, AstraZeneca Ltd, Macclesfield
• Dr John Carr, University of Cambridge
• Dr Martin Carrier, Queen Mary College, London
• Dr Peter Coyle, Regional Virology Laboratory, Belfast
• Professor Ernest Gould, Centre for Hydrology and Ecology, Oxford
• Dr Penny Hirsch, Rothamsted Research, Harpenden
• Dr Keith Howard, Baxter Vaccines, AG, Austria
• Professor David Lewis, St George’s Hospital, London
• Dr Philip Minor, National Institute for Biological Standards and Control
• Mr Robert Osborne, University of Glasgow
• Dr Brian Robertson, Imperial College, London
• Dr Peter Searle, University of Birmingham
• Dr Michael Skinner, Imperial College, London

Members’ biographies and interests may be found on the SACGM(CU) website.

At the end of 2006, resignations were received from one bacteriologist, one plant biologist and the NGO member. It is intended to fill these vacancies in the coming workplan for 2008.

Working Groups

A number of working groups composed of specific Committee expertise were established during 2006 and operated throughout 2007 for the purposes of writing and updating SACGM guidance, previously published in 2000. The composition of each working group is detailed in Appendix 2.

Interactions with other committees

The Secretariat maintains strong links with a number of other scientific advisory committees. Furthermore, several members also sit on these committees, namely:

• The Advisory Committee on Dangerous Pathogens (ACDP)
• The Advisory Committee on Releases to the Environment (ACRE)
• The Gene Therapy Advisory Committee (GTAC)

The Committee frequently invites members from these committees to its meetings in order to inform their discussions on relevant and some of the more contentious agenda items. It is proposed to build upon this by including updates from cross-representing Committee members as part of the Secretariat Report. It should be noted that the Vice Chair of the Committee is also the Chair of GTAC.

Key business during 2007

10th Meeting of SACGM(CU) on 1 February 2007

The 10th meeting was also the 2nd open meeting of the Committee. The meeting was attended by approximately 70 people including HSE’s Chief Executive and HSE’s Chief Scientist.

The main business of the meeting was to launch the revised version of the SACGM(CU) Compendium of Guidance. The revision had taken place over the preceding two years, through a number of specialist working groups, which advised on the redrafting of the guidance.

The Compendium of Guidance is recognised across Europe as a source of advice on the contained use of genetically modified organisms. A number of Member States have requested presentations on the Compendium to be appraised of the precedent setting advice contained within it, for example, classification of viral replicons, interpretation of siRNA in the context of GM definitions.

11th Meeting of SACGM(CU) on 28 June 2007

At the 11th meeting, members advised upon a number of matters including:

• the status and classification of Herpes Simplex Virus (HSV) 1716
• the Guide to the GMO(CU) Regulations
• exemption of safe organisms from GMO(CU)

Status and classification of Herpes Simplex Virus (HSV) 1716

The development of novel gene therapy vectors brought a particular construct to the attention of the Committee. A company producing a deletion mutant of HSV requested that the CA reclassify this virus as a non-genetically modified organism. The producers asserted that in Germany, HSV 1716 was not considered to be genetically modified and therefore was out of scope of the German GMO(CU) legislation. Based on this precedent, it was argued that the UK CA should allow the product to be exempted from the GMO(CU) regulations. Alternatively, the producers argued that the virus was attenuated and required, at most, to be handled at containment level (CL) 1.

The outcome of discussions following a presentation to the Committee by the company resulted in advice to the CA that it considered the virus to be derived through genetic modification techniques and therefore was not exempt from GMO(CU) regulations. However SACGM(CU) agreed that the evidence submitted supported the request to down grade the work to CL1.

Revision of the guide to the regulations

Having completed the revision of the SACGM(CU) Compendium of Guidance, the next substantive item in the Committee’s workplan was the redrafting of the guide to the regulations, which, written to support the regulations that came into force in 2000, did not include amendments added in 2005. The update was deemed necessary to ensure that the guide accurately reflected changes in legislation and technological developments. The Secretariat presented an early draft to the Committee for comment.

The outbreak of foot and mouth disease following release of the virus from the Pirbright site in July 2007 impacted on the redrafting of the guide to the regulations in two ways.

• The Secretary, in his role as HSE Specialist Inspector was called upon by the Secretary of State for Environment to lead the investigation into the potential breaches of containment that were implicated in the cause of the outbreak;
• The subsequent investigation report and review of the regulatory framework for handling human and animal pathogens, recommended a single regulatory framework for all contained use of biological agents encompassing human, animal and genetically modified pathogens, which will potentially subsume the GMO (CU) regulations.

Consequently, the guide to the regulations is currently in abeyance until a mechanism for implementing a single regulatory framework has been decided upon.

Exemption of safe organisms

An ongoing commitment from the Committee is to assist the CA in developing a less bureaucratic system for the exemption of safe organisms in line with the criteria outlined in the European Commission (EC) guidance. Despite the matter being raised at meetings of the European Commission CAs, a satisfactory conclusion has yet to be reached. This is an ongoing workstream.

12th Meetingof SACGM(CU) on 28 November 2007

At the 12th meeting, members advised upon a number of matters including:

• classification of influenza virus with altered host range;
• advice on a needlestick injury involving a GM animal pathogen.

Connected programme of work investigating the pathogenicity and transmissibility of influenza viruses

The Committee was invited to advise on a programme of research, the aims of which will be to understand how influenza causes disease and transmits from one host to another. The purpose of the work includes enhancing the scientific ability to predict the threat of a pandemic and to develop improved vaccines and therapies. The work would involve the use of a range of engineered viruses and wild-type viruses, commencing in a step-wise manner from low to high hazard activities, with consequently increasing levels of containment.  The highest hazard work may involve the engineering of specific mutations to change the host range of avian influenza to human host and human influenza to avian host.

The Committee considered the scientific content of the associated risk assessments for this work and the adequacy of the proposed containment.  The Committee concurred with the indicated levels of containment and was comfortable with the approach being proposed.

Accident involving a genetically modified bacterium

The Committee was appraised of an incident investigated by HSE in its capacity as regulator of contained use activities, in which a worker suffered a percutaneous injury to a finger, whilst working with a GM animal pathogen, Actinobacillus pleuropneumoniae. The severity of the reaction to the infection resulted in considerable tissue damage. HSE approached the Committee for advice on whether the severity of the reaction was connected to the type of genetic modifications made to the bacterium.

The Committee was of the opinion that the pathology seen was not due to how the bacterium had been modified, but rather the artificial route of exposure to the pathogen, i.e. a high titre of respiratory pathogen delivered subcutaneously, coupled with the restricted nature [blood supply] of the wound site.

Future Work

In addition to the normal ‘reactive’ business of the Committee, the workplan for 2008/09 will include the following topics:

• Contribution to the formulation of a common set of containment measures for human and animal pathogens;
• Emerging topic of ‘Synthetic Biology’ will be advised upon from a risk assessment perspective;
• Classification of retro- and lentiviral vectors – consideration of the inherent hazards of these vectors;
• Publication of advice on the use of reverse genetics for formulation of seasonal influenza vaccine;
• Recruitment of new Committee members to restore the membership to full cadre;
• Development of simplified procedure for the exemption of safe organisms from the GMO(CU) regulations;
• Input into the development of a single regulatory framework for human, animal and genetically modified pathogens

Appendix 1: United Kingdom Competent Authority Role

Health and Safety Executive (HSE): HSE has lead responsibility for human health and safety throughout Great Britain. HSE administers the permissioning process for the whole of the competent authority, and its Biological Agents Unit (BAU) maintains the Public Register and provides technical comment on the notifications. HSE’s BAU undertakes inspections of notified premises and activities to check compliance and support the GMO(CU) regulatory framework. Permissioning provides intelligence for inspection and inspection provides intelligence for permissioning.

The Department for the Environment, Food and Rural Affairs (Defra): Acts on behalf of the Secretary of State. It has lead responsibility in England and Wales for all effects from the contained use of GMMs on the environment or living organisms supported by the environment, including indirect effects on human health that may result from environmental pathways. It is also responsible for the environmental effects of GM animals and plants in England and Wales in relation to contained uses that affect the former MAFF's interests, e.g. farmed animals (including fish and shellfish), plant varieties and seeds, veterinary medicines, fertilizers, animal feedstuffs, food and forestry, as well as the marine environment.

The Scottish Executive (SE): Has the same responsibility in Scotland for the effects of contained use of GMMs on the environment as Defra has in England and Wales, and for the environmental effects of GM animals and plants as Defra has in England. It is also responsible for those aspects of public health that do not come within the scope of the HSWA.

The Welsh Assembly Government (WA): Has no legal responsibilities for contained use activities involving GMMs, but are consulted upon the environmental aspects of such activities when they occur in Wales. The assembly has the same responsibility for the environmental effects of GM animals and plants in Wales, as Defra in England or the Scottish Executive in Scotland. This means that they have a legal responsibility to comment on environmental aspects of contained use activities involving GM animals and plants.

 

Appendix 2:  SACGM Working Groups

Clinical Trials Working Group

Dr Martin Carrier
Dr Peter Coyle
Professor Martin Gore
Dr Peter Searle

Containment and Control Working Group

Professor Janet Bainbridge
Dr Gary Burns
Dr Martin Carrier
Mr Robert Osborne
Dr Brian Robertson

GM Risk Assessment Working Group

Professor Janet Bainbridge
Dr Gary Burns
Dr Martin Carrier
Dr Brian Robertson

Plants Working Group

Dr John Carr
Professor David Baulcombe
Dr Penny Hirsch
Professor James Dunwell (co-opted from ACRE)
Dr Androulla Gilliland (Defra departmental assessor)

Viruses Working Group

Dr Martin Carrier
Dr Peter Coyle
Dr Ernest Gould
Dr Keith Howard
Dr Philip Minor
Dr Peter Searle
Dr Michael Skinner
Dr Jonathan Stoye (co-opted from ACRE)

Abbreviations

ACDP

Advisory Committee on Dangerous Pathogens

ACRE

Advisory Committee on Releases to the Environment

ATCSA

Anti-Terrorism,Crime and Security Act 2001

BAU

BiologicalAgents Unit

CA

CompetentAuthority

CL

ContainmentLevel

CoPSAC

Codeof Practice for Scientific Advisory Committees

COSHH

Controlof Substances Hazardous to Health

Defra

Departmentfor Environment, Food and Rural Affairs

DH

Departmentof Health

DSTL

Defence,Science and Technology Laboratory

EA

EnvironmentAgency

EC

EuropeanCommission

GM

GeneticModification

GMM

GeneticallyModified Micro-organism

GMO

GeneticallyModified Organism

GMO(CU)

GeneticallyModified Organisms (Contained Use) Regulations

GTAC

GeneTherapy Advisory Committee

HG

HazardGroup

HID SI4

HazardousInstallations Directorate, Specialised Industries Division 4

HPA

HealthProtection Agency

HPAI

HighlyPathogenic Avian Influenza

HSE

Healthand Safety Executive

HSENI

Healthand Safety Executive NorthernIreland

HSL

Healthand Safety Laboratory

MHRA

Medicinesand Healthcare Products Regulatory Agency

NGO

Non-GovernmentalOrganisation

NIBSC

NationalInstitute of Biological Standards and Control

SACGM(CU)

ScientificAdvisory Committee on Genetic Modification (Contained Use)

SG

ScottishGovernment

siRNA

small interfering ribonucleic acid

NAW

NationalAssembly for Wales

WHO

WorldHealth Organisation