2.1. Special characteristics of microbial genetic resources (MGRs)

In contrast to higher plants and animals, microbial genetic resources replicate frequently. Consequently, this may lead to changing populations in the environment and also ex-situ in culture collections, if not expertly preserved. They cannot be accurately enumerated, thus an estimation of a ‘base line’ for inventorying purposes is not possible. Microorganisms are easily transferred across borders by wind, water, the movement of animals or humans and cannot be tracked and monitored conventionally. They are difficult to fingerprint for identity or non-identity checks. On the other hand, again in contrast to e.g. plants, they are unlikely to be depleted by sampling; however, the loss of hosts (plants or animals) could lead to the loss of dependent microbial species; examples are already known for fungi. With a view to global distribution and political borders, strains of one and the same microbial species have been recorded to occur in a number of geographical locations. Few species may occur in only one country. Isolates or strains within a species may show slight genetic variation (which may also e.g. depend on sampling time), therefore individual isolates are of considerable significance in terms of genetic expression. Microorganisms easily develop novel and valuable properties in response to environmental stress, this is one of the reasons why they may be found equally in ‘gene-rich’ countries as in ‘industrial’ regions. Finally, besides requiring taxonomic skills, the study of microorganisms requires extensive, special equipment and technologies.

All these characteristics of microorganisms, together with the existing technical limitations and natural realities need to be taken into consideration when CBD issues such as Country of Origin or Access and Benefit Sharing regimes are discussed.

2.2. Potential hazard posed by microbial cultures

An important characteristic of microorganisms impacting upon the work with them is the potential of some of them to cause harm to humans, animals, plants or the environment. According to the potential risk associated they are classified into risk groups and/or governed by quarantine, sanitary, import and export regulations. As one of the most comprehensive examples the EU Risk Group allocation (EC Directive 93/88/EEC, with a view to harm to humans, listing risk groups 2, 3 and 4) of bacteria and fungi is presented here. EU member countries may decide to allocate a particular organism to a higher risk group than indicated in the EU Directive but not to a lower one. It can be seen that for bacteria and fungi the largest percentages are covered by those organisms with no or only minor harmful potential. Only <1% (Bacteria, Figure 1) and <0.01% (Fungi, Figure 2) are allocated to the pathogenic group RG3. Of these organisms, none are classified in RG4.

Interestingly, in the case of the high risk bearing Risk Group 3 or 4 organisms there is, in the EU and worldwide, consensus on how to handle these. More difficult, from the point of view of service collections, is the situation with those organisms allocated in Europe to Risk Group 2 – a quite diverse group of organisms – where the classification of some of them is (as indicated above) handled differently in the various countries. This results in quite differing demands for the mode of packaging, administrative paper work, accompanying documentation, etc., depending on sender’s and recipient’s countries. Such differing demands place heavy administrative burdens on service culture collections and slow down or even impede delivery/supply of biological material.

2.3. Benefits and applications of MGRs

Microorganisms have an endless array of capabilities ranging from the degradation of compounds to the synthesis of secondary metabolites. Applications for countless processes, experiments and all sorts of ‘situations’ can be listed. Be it enzymes such as those found in the group of aerobic endo-spore forming bacteria, be it their spores themselves which can be applied in such diverse fields as agriculture or human health. Microorganisms play a major role in providing basic material for the development of pharmaceutical drugs, in biotechnology, for bioremediation and bio-control agents, food and drink, toiletries and products for a number of other industries. It has proved difficult to estimate the value of these resources but, as an example, the estimated annual global market for products basing on biological resources in these branches reaches 500–800 Mrd US$ (TenKate and Laird 1999).

Finally, one should not forget the immense role that microorganisms play in the environment with their diverse abilities to either degrade or synthesize a wide range of compounds. Nutrient cycles would not function without microbes at the basis of the transformation chain, and ultimately, the fertility of soil, the climate and our life depend on them.

3.1. Cultures of MGRs in collections: what knowledge do collections store, what do collections do with the deposited biological material?

Typically microbial genetic resources are isolated and identified (if not sent in by a depositor), or authenticated, possibly studied additionally, deposited, maintained/conserved and subsequently distributed to the user community. Each MGR held in a culture collection is allocated a unique identifying code; this ‘strain identifier’ remains constant even in case of taxonomic changes. Records of depositors, taxonomic information and other properties have usually always been kept for scientific reasons, as well as records of recipients of biological material for legal reasons. Additional information, such as the person(s) involved in the isolation and identification, the date of isolation, the country of origin, etc. is routinely recorded since 1993, the date of coming into force of the CBD. Before that date this information may not always be available. Records in service collections are usually more complete than those of in-house research collections.

Information concerning the biological material provided by the depositor and published in literature is usually made available to the public from the collections’ catalogues or homepages together with information on how to grow the organisms. This is one of the scientific services rendered by service culture collections.

3.2. Cultures of patent-MGRs in collections

In contrast to the biological material listed in the publicly accessible catalogue collections, information on the biological material deposited in connection with patent applications is sparse.

MGRs have to be deposited for full disclosure of an invention when patent protection is sought for a product or process. In these cases, the organisms are not always completely identified, patent law normally does not ask for taxonomic identification. However, as a depositary may need to know with what they work, e.g. for safety reasons, some basic information is supplied to them. Other pieces of information, such as country of origin, source of isolation, date of isolation, isolator, etc. are usually not indicated. To date, the European Patent Law does not require this information to be included in the patent documentation (EU Directive 98/44/EC), but e.g. the Norwegian Patent Law (Norwegian Patents Act, Section 8 b.) does require information on the country of origin or the providing country and on the obtained prior consent. Biological material deposited for patent purposes is supplied only according to applicable patent regulations (internationally, this is the Budapest Treaty; nationally individual national patent law applies). This embraces e.g. not being available before publication of documents; after publication being available only according to certain administrative processes. When samples are delivered to entitled parties, a notification is sent to the depositor. All information provided to the depositary is held strictly confidential by the depositary unless release of information is explicitly allowed by the patent regulations. The status of International Depositary Authority (IDA) according to the Budapest Treaty requires recognition through WIPO and involves high organizational requirements for the culture collections holding this status. Most restrictions to availability of the biological material and information usually apply in dependency from the life of the patent. More details on the handling of patent deposits in culture collections may be found in older literature (e.g. Fritze 1994; Fritze and Weihs 2000; Fritze and Weihs 2001).

4.1. Biosafety and biosecurity regulations

Existing measures for biosafety and – not least – the knowledge that such measures exist, provide the basis for any emerging biosafety/biosecurity discussion and development.

A well-known source is the World Health Organization. Their WHO Laboratory Safety Manual (3rd ed. 2004; WHO/CDS/CSR/LYO/2004.11) is a valuable background information document for any work with biological material. More recently WHO published the WHO Biorisk Management Laboratory Biosecurity Guidance (2006, WHO/CDS/EPR/2006.6).

Transport and packaging of living biological material is governed by various national, regional and global legislations. E.g. Accord Européen Relatif au Transport International des Merchandises Dangereuses par Routes (EU ADR) or UPU Regulations for Postal Services. The shipping of potentially hazardous materials are internationally covered by the IATA Dangerous Goods Regulations (IATA 2005). If respective cultures are not packed adequately, the shipper may be faced with drastic penalties.

Each country or region may have their import/quarantine regulations of relevance to their valuable agricultural products, be it crops or livestock. Widely accepted Risk Group allocation for microorganisms (RG 1–4) has been done on the basis of potential harm to human workers. While in the EU document EC Directive 93/88/EEC on Biological Agents, only RG 2–4 are listed, the German Brochure ‘Merkblatt Sichere Biotechnologie’ (Note on Safe Biotechnology), not only lists all 4 RGs, but also abundant information is provided on potential pathogenicity to e.g. fish or insects (in particular bees), cloven-hoofed animals, plants, etc. Additionally, general information on how to assess the risk associated with a particular organism is presented.

Particular handling permits are required for the various kinds of hazardous organisms and microbial culture collections must promote a sense of security in order to reduce the probability that dangerous biological material is obtained by unauthorized persons. Coming with this is also a duty of care to perform risk assessments.

Unfortunately, in the academic circles, this sense of security is often missing, and knowledge and acceptance of the various regulatory requirements even in the classical field of biosafety is low. And it should be kept in mind that many of those laws and guidance established under the term ‘biosafety’, also widely cover the area of ‘biosecurity’; such as the release of dangerous biomaterial within the EU is regulated for some time through the EU Dual-use legislation (EU Council Regulation 3381/94/EEC).

A European Bio-Preparedness Workshop (hosted by EuropaBio, Brussels, September 2007) had the main objective to provide input to the EU Commission for the Green Paper on Bio-Preparedness (COM(2007)399 final) which will have a strong impact on all institutions working with living biological materials. Transport, traceability, import, export and the dual-use aspects of biological materials are key issues of the discussion. Large parts of the scientific community have been criticising the approach of putting even more regulations in place as the biosecurity risk seems neglectable. On the other hand, biosecurity measures are regarded as preventive and harmonised European or international rules seem desirable especially for the higher risk groups of microorganisms. A consultation process has been started by the EU Commission in order to weigh different approaches towards a European Bio-Network as an advisory structure on biopreparedness.

Input was given from the collections’ side to the CEN Laboratory Biorisk Management Standard Document (CEN/WS 31 N28) through WFCC and individual national routes. This reflects the status quo of an international initiative on setting rules for implementation of best practice in the area of biosafety and biosecurity. Following a consultation period, the standard document was agreed by a consensus procedure at the third and last plenary workshop (WS 31, 28/29 November 2007, Brussels). The resulting CEN Workshop Agreement (CWA 15793:2008) has a voluntary status. The document may be used as a guidance for auditing and certification processes and it may support the WHO laboratory guidelines mentioned above. It is performance-based and does not deliver technical elements avoiding citation of legislation or regulations. After a period of three years a new decision will be taken on either transforming the document into a CEN standard, or entering it into the ISO frame or to possibly withdraw it again.

A more recent relevant activity, administered through the OECD by a special Task Force on Biological Resource Centres, has as its aim the transition of traditional microbial culture collections to biological resource centres to meet the academic and industrial communities’ needs in the 21st century. One key element in this was the development of Guidelines relating to biosecurity in the work of BRCs. The agreed biosecurity document has been declassified and became officially available by early 2007 and is part of the complete OECD Best Practice Guidelines (BIO(2007)9FINAL.pdf). The guidance relates to all bio-material domains and reflects the inherent dual-use potential of bio-material and its information. It nevertheless seeks the balance between “promoting scientific openness and a sense of security” and tries to deliver a “balanced and mutually reinforcing effect”.

The emerging biosecurity debate needs to be accompanied by the expert knowledge available in collections and the academic community as well, as, in the end, their research work will be influenced as well. Such legislation is being developed and in the EU efforts are being made to be able to react on a common EU level. These will have a major impact on collections, the work of which vitally depends upon international exchange. It would certainly be sensible, before developing new regulations, to first review existing legislation that is relevant to biosafety and biosecurity. Here, the outcomes of previous cooperations between European culture collections, such as CABRI (Common Access to Biological Resources and Information, www.cabri.org) and EBRCN (European Biological Resource Centre Network, www.ebrcn.org) could prove useful.

4.2. Provisions of the Convention on Biological Diversity (CBD) and articles of relevance to culture collections

Already in the mid-90s it was recognized that the demands of the CBD for maintenance and sustainable use of biodiversity, and the equitable sharing of knowledge, technology and benefits resulting from the use of biodiversity would directly influence the work of ex-situ service culture collections whose custodial responsibilities would need to be defined more clearly in the future. In particular, it was understood that the Convention on Biological Diversity had altered the way in which individuals, scientific institutions and private companies were entitled to access genetic resources. As a consequence, ex-situ collections face an evolving legal and policy regime governing access to genetic resources at both the international and national level. They will need to adopt new and flexible approaches to adapt to recent developments. The main questions to solve remain:

• How should ex-situ collections tackle the issue of acquiring new material?
• How do the access provisions of the Convention on Biological Diversity affect scientists in their day-to-day work?
• How should ex-situ collections respond to the need to define rights and responsibilities of source countries, managers of collections and the academic and corporate scientists using them?
• How should ex-situ collections tackle the issue of supply of material to others and the relating terms of delivery?

4.3. Articles of the CBD of particular relevance to microbiology and culture collections

All Articles contain a statement saying that contracting parties agree to support the aims of each Article ‘as far as possible and as appropriate’ allowing room for flexibility depending on national circumstances. Each Article also includes a statement indicating the special needs of developing countries. In the following only those Articles are listed, which are of particular relevance to microbiology and culture collections. The relevant terms or wordings have been additionally highlighted.

5.1. Culture collection initiatives towards general operational and legal requirements

An early example for an attempt to lay down common principles is the WFCC voluntary Guidelines (WFCC 1992). These provide a framework for the establishment and operation of collections of cultures of microorganisms. Recommendations are given on the managerial and laboratory level:

1. organization and funding of a collection including objectives and holdings as well as staff
2. deposit procedures, culture authentication, preservation and culture supply
3. other services, such as documentation and computerization, catalogues, research and training, safety and quality standards and national and international collaboration

Not least, the WFCC has developed a database system in the World Data Centre for Microorganisms where its members are registered through a unique acronym and numerical identifier in its official list and is urging them to catalogue their microbiological resources. This system allows the tracking of microbiological items which must be possible with a view to the requirement of Access and Benefit Sharing of the CBD.

5.2. Approaches to the topic of access to ex-situ microbial genetic resources under the CBD

In 1996, a WFCC Information Document (Access to ex-situ Microbial Genetic Resources within the Framework to the Convention on Biological Diversity) was produced as a Background Document to the UNEP/CBD/COP/3/Inf. 19 information document. This tried to convey to governments, policy makers and microbiologists issues relating to access to ex-situ microbial genetic resources. A survey of some 500 culture collections worldwide was provided giving an account on their role, organizational and administrative regimes, distribution policies and access practices. Information was provided on the special characteristics of microorganisms that distinguish them from plants and animals and the consequences of such characteristics for inventorying, tracking and benefit sharing. Existing relevant legislation and operating practices were summarised and policy issues addressed. Among a series of recommendations given was e.g. that access to ex-situ microbial genetic resources should remain unimpeded for the purposes of scientific research, industrial application, education and health care. Another item related to the development of a voluntary code of conduct for the introduction of access and benefit sharing procedures (http://wdcm.nig.ac.jp/wfcc/InfoDoc.html).

More recently the MOSAICC project (Micro-organism Sustainable Use and Access Regulation International Code of Conduct) took up the recommendation from the previous publication and continued the work on the development of operational guidelines for the introduction of access and benefit sharing procedures. It took into consideration the CBD requirements that (1) Prior Informed Consent (PIC) should be obtained before collection of genetic resources and their deposit in a resource centre and (2) that terms should be defined at the time of deposit which will cover distribution to third parties. Model Material Acquisition Agreements and model Material Transfer Agreements have been developed with respect to microbial cultures for the use of culture collections as well as of research scientists in their role of depositors or recipients of cultures (http://www.belspo.be/bccm/mosaicc).

Initiated from the ECCO platform, an EU funded project EBRCN (European Biological Resource Centres Network) concentrated on the compilation and publication of focussed information documents (www.ebrcn.org) trying to broadly cover the various legal requirements with which modern day microbial collections are challenged. These may be adjusted to national legislation or to collection-specific requirements as the case dictates and may be used by non-collection institutions as well. Subjects were:

• Classification of Microorganisms on the Basis of Hazard
• Quarantine Regulations
• Convention on Biological Diversity (CBD)
• Intellectual Property Rights
• Safety Information Sheet for Recipients of Microorganisms
• Regulations governing Packaging and Shipping
• Control of Distribution of possibly dangerous Microorganisms
• Health and Safety Requirements

While being highly useful, these documents require constant up-dating to be of effective actual help above a purely informative character.

6.1. Core contents of an ECCO agreed MTA

Taking the various aspects of responsibilities of BRCs into account and the obvious need for harmonized approaches, an ECCO working group was formed in 2005 to develop a document that would cover all relevant aspects that apply when a sample of a biological material is supplied by a culture collection to a recipient. Under the coordinating leadership of Dr. Danielle Janssens, BCCM-LMG, this group worked on the development of a document that would show to all parties involved, that all important issues with regard to the availability and use of the material are handled in the same way by the many different European collections, and that variation in handling between culture collections would concern only minor aspects.

It was not unanimous from the beginning whether such a separate document was needed. The term of ‘MTA’ Material Transfer Agreement was coined only recently and many of the types of records kept at collections would have met the definition of an MTA.

Thus early discussion revolved around the questions:

• What is an MTA?
• What purpose shall an MTA serve?
• What does the CBD expect?
• Do service CCs need an explicit MTA to serve the spirit of the CBD?
• What is already covered by existing documentation and procedures: catalogues, lists, order forms, accession forms, delivery slips, conditions of sale and delivery, etc.?
• Can there be a solution in the case of restrictions imposed on exchange for bacterial type strains which have a very specific use?
• What kind of experience have CCs had with their existing MTAs?

However, discussions resolved that it was deemed necessary to agree to common definitions and procedures, not least with the aim to facilitate exchange of biological material among collections. Thus, taking into consideration the varied nature of collections in their development and with a view to holdings, scope, parent bodies and financial dependencies it was agreed that the ECCO MTA should be developed to form a basic core agreement on key issues, to which the individual collection could add its own specific requirements.

The group first met at a workshop at the DSMZ in Braunschweig in 2005. Since then, the document went through several rounds of e-mail discussions and was presented and further discussed at the Annual ECCO Meetings until a final version was agreed early 2009 (www.eccosite.org). Triggered through the various legal developments outlined above, the topics to be covered in the Agreement were agreed to be points of core relevance to all collections to which they are required to develop a position. Topics revolve around a selection of subjects, reflecting daily practice in the supply of living biological material and the awareness of a level of responsibility at culture collections. These were:

• Safety and security

These aspects were taken into account with a view to the recipients of samples of biological material: their entitlement to receive samples, their being informed on potential risks associated with samples, their responsibilities when handling these samples.

• Traceability of samples of biological material

Transparency of the movements of microbiological resources between source country and end use is central to the requirements of the CBD, for safeguarding individual collections as well as for securing countries’ access and benefit sharing (ABS) rights.

• Quality of biological material

The core reason for the existence of culture collections is to provide access to high quality biological resources and validated information. Collections maintain and supply authentic materials that are preserved in a stable condition and they make them available for long-term use, ensuring continuity. Once materials move away from such an environment there is the possibility of strain drift, contamination or replacement of the strain. It must be ensured that the scientific user community receives high quality materials on which to base their research and that donors have their investments protected.

• Fair and equitable benefit sharing

Here the rights of the country of origin are concerned according to the CBD, and rights of the institutions entitled to be involved. At the same time free use for research purposes is stated. Possibly, this part of the document needs to foresee amendments that might be triggered from the COP 10 (Japan, 2010) decisions towards ABS. COP 9 advocated a road map to ‘sectoral’ approaches to ABS and – depending on how ‘sectoral’ will be defined – this will heavily impact on the microbiological sectors.

• Intellectual property rights

The main point here is to inform recipients of biological material that they have no immediate rights to the received material other than working with it. It does not discuss the issue of generating further intellectual property.

The length of discussions spent on careful definitions of the terms used in the document reflect the special difficulties that arise when natural scientists have to deal with legal issues, the general difficulty to agree on meanings of terms, especially in an international environment and the common understanding of the importance of the issues and their consequences.

For example it was felt necessary to precisely define whom a particular biological material would be sent to, who would be the recipient of this material. Besides the broad covering of the recipients’ requirements from a scientific and regulatory point of view (e.g. appropriately equipped laboratory, appropriately trained personnel, handling responsibilities, restrictions), it was also defined how the potential transport chain should be kept traceable and safe:

RECIPIENT: The party to whom the COLLECTION sends the MATERIAL. In case this is not the END-USER but an INTERMEDIARY, this INTERMEDIARY agrees (i) to forward to the END-USER the present MTA and the MATERIAL in unchanged form and quantity as received from the COLLECTION, and (ii) to use for this further shipping the proper packaging, a trained shipper, and an authorized carrier, according to the applicable laws and regulations.

To be able to define the sphere of action of this MTA, it was then as well felt necessary to define what the term material would embrace. The listed individual (sub)terms were further on explained in more detail.

MATERIAL: ORIGINAL MATERIAL, PROGENY and UNMODIFIED DERIVATIVES. The MATERIAL shall not include MODIFICATIONS.

A core aspect of this MTA is that the exchange of biological material for research purposes and thus between collections should not be impeded. Therefore a definition for this kind of exchange was deemed necessary:

LEGITIMATE EXCHANGE: The transfer of the MATERIAL between scientists working in the same Laboratory, or between partners in different Institutions collaborating on a defined joint project, for non-commercial purposes. This also includes the transfer of MATERIAL between public service culture collections/BRCs for accession purposes, provided the further distribution by the receiving collection/BRC is under MTA conditions equivalent and compatible to those in place at the supplying collection.

A broad sector in the agreement is devoted to biosafety and biosecurity aspects, both subjects being central to the work with microorganisms. Thus, a number of clauses have been included to underline the responsibility of the recipients, e.g.:

3. RECIPIENT agrees that any handling or other activity undertaken in their laboratory with the MATERIAL will be conducted under their responsibility and in compliance with all applicable laws and regulations.

4. RECIPIENT therefore assures that within their laboratory (i) access to the MATERIAL will be restricted to personnel capable and qualified to safely handle said MATERIAL and (ii) RECIPIENT shall exercise the necessary care, taking into account the specific characteristics of the MATERIAL, to maintain and use it with appropriate precautions to minimize any risk of harm to persons, property, and the environment, and to safeguard it from theft or misuse.

On the side of the providing collection lies the responsibility for the quality of the provided material. Thus, a clause is included that the collection undertakes to guarantee certain properties of the material within limits.

10. The COLLECTION hereby assures within the scope of its quality system and as far as can be determined through the COLLECTION’s test regimes, that the MATERIAL shall be viable and pure upon shipment from the COLLECTION.