Team:Reading/Human Practices

Regulatory challenges of rooftop installations

Contents

An important part of iGEM is thinking about the wider impact of your project. We considered whether it would be possible to set up our cyanobacterial solar panels on roofs at Reading or on people’s houses. This meant coming up with a design for a larger photovoltaic cell, considering the biosafety issues involved, and what regulatory challenges we would face.

Introduction

Creating a cyanobacterial photovoltaic cell and getting it installed on a roof at a university presents a number of challenges. The design of the system is the first aspect to consider. We look into design and cost of the parts on the Fuel Cell page. Then there are European Union (EU) and government regulations and, in the case of Reading, several boards and internal committees through which applications would have to pass. We consider these in this section. Each of these raises questions about biosafety, such as potential effects of the escape of our organism into surrounding environments. We answer these in the safety section. In addition to using our technology at our own university, we also considered commercialising the technology and installing it on people’s houses. This opens up a new realm of issues, such as getting our energy source classed as renewable according to the EU’s Renewable Energy Directive (RED), and getting permission for having GMOs on many distinct properties. These wider problems are also reviewed here.

Many sections of our report will be applicable to other teams considering contained use of GMOs, and we hope future teams will benefit from our research. The EU section will be particularly relevant to other EU member states, as the EU regulations form the common minimum requirements for each country. In general, this page and the safety page should guide teams considering biosafety issues associated with cyanobacteria; there are currently no reviews of biosafety in synthetic biology of cyanobacteria that we are aware of. We finish with a roadmap for those thinking about whether they could commercialise a genetically modified microorganism (GMM)-containing system, especially as a renewable fuel source.

It should be noted that the report mainly refers to contained use of GMMs. Though our system is contained, parts of it could be considered to overlap with deliberate release (discussed below). We have therefore focussed on regulations pertaining to contained use, but have referred to those on deliberate release where our system could potentially fall under its purview. Due to this relevance, and partly time due to time constraints, we have not exhaustively considered deliberate release or contained use categorised as class 2 or above.

1. Introduction
2. Levels of Regulation
3. EU Regulations
• Introduction
• Contained Use
• Deliberate Release
4. UK Regulations
• Introduction
• Contained Use
5. Other Regulations
6. Findings and Conclusions
7. The Roadmap
8. Resources
9. Acknowledgements

The Different Levels of Regulations

At the highest level, the Cartagena Protocol on Biosafety covers living modified organisms (LMOs) and their transport across borders. This is an international United Nations agreement that has been in place since 2003, and is implemented in the EU by Regulation EC 1946/2003. Below that, the EU issues “directives” on genetically modified organisms (GMOs) that must be implemented by all EU member states. For contained use, only the state’s regulations need to be considered; there is no involvement at the EU level. For deliberate release, rules are much more complicated, involving notification of the European Commision (EC). There are also other EU regulations governing GM food that will not be covered here. In the UK, the EU directives are implemented by the Department for Environment, Food and Rural Affairs (DEFRA) and the Health and Safety Executive (HSE). Finally, at Reading we would have to pass at least 3 committees - including the sub-committee for biological safety, the project committee, and the environmental committee - in addition to getting approval from the building manager.

EU Regulations

Introduction to EU Regulations

The two EU directives concerning our plans are the directive 2009/41/EC on contained use and the 2001/18/EC directive on deliberate release of GMOs. Of these, the contained use directive is probably most appropriate, though it is possible that the deliberate release directive may be relevant too. The 2009/41/EC directive defines contained use as: “any activity in which micro-organisms are genetically modified or in which such GMMs are cultured, stored, transported, destroyed, disposed of or used in any other way, and for which specific containment measures are used to limit their contact with, and to provide a high level of safety for, the general population and the environment”, in Article 2(c).

By contrast, the 2001/18/EC directive defines deliberate release as: “any intentional introduction into the environment of a GMO or a combination of GMOs for which no specific containment measures are used to limit their contact with and to provide a high level of safety for the general population and the environment”, in Article 2(3).

By comparing these, and reviewing the proposed implementation of our idea (link), we can see that we would most likely fall under the contained use directive because of our suggested containment measures. Our technology will use all of the activities specified by contained use, and implement appropriate safety measures. Based on this, we shall chiefly address contained use regulations, but mention rules on environmental release that are significant.

EU: Contained Use

In summary, class 1 contained use requires:

• a risk assessment
• classification of the risk of the GMM according to the assessment
• appropriate containment
• notification of the relevant authority
• an emergency plan for accidental release

We shall explore each of these points in further detail.

Article 4 defines one of the main requirements for contained use: for a risk assessment to be carried out (Article 4(2)), in accordance with the guidelines in Annex III, with the aim of classifying the GMM. The criteria include assessing the potential to cause disease, effect on the environment (Annex III (A1)), and harmful effects of the genetic material, recipient, donor, vector and final GMM (Annex III (A2)). The severity of these issues and the chance of them happening must also be analysed. As a non-pathogenic organism, capability of causing disease is not relevant to our organism. The most germaine section is in Annex III (A1), which lists considering “deleterious effects due to establishment or dissemination in the environment” and “deleterious effects due to the natural transfer of inserted genetic material to other organisms.” Annex III (B7) goes on to require that the proposed use of the microorganism be combined with the above assessment in assigning it to a class. “Non-standard operations” is mentioned as affecting classification (Annex III (B7 iii)); this term is ambiguous, but may encompass our suggestion of having GMMs on roofs of private properties. Our drip-in/drip-out system (link), with the filter needing autoclaving upon replacement, may also fall under non-standard use. This would need to be taken into consideration if attempting to use our technology commercially. From this, it is clear that our GMM belongs in class 1 (as defined in Article 4(3)), so requires level 1 containment measures, though any doubt raised from our “non-standard operations” might cause a more strict classification (Article 4(4)). For those wishing to classify their organism, Directive 2000/54/EC can be referred to, or classification systems of the specific country.

The risk assessment has a particular focus on waste disposal (Article 4(5)), making our drip-out waste disposal system very important (link). As removing the filter from the panel might be a source of accidental release, careful planning of waste management should be high on our priority list. The final risk assessment must be given to the competent authority (Article 4(6)) - HSE in the case of the UK. Containment measures are defined in Annex IV.

Article 6 poses a potential issue. It requires notifying authorities upon contained use at each new property. While this is reasonable for single use at the university, our idea of having installations on separate houses would mean giving the information listed in Annex V for each site, including the risk assessment, which individuals are responsible for supervising, and a description of the premises. This would mean that the risk assessment must be sufficiently comprehensive to envision all potential environments where an installation may be set up, and would mean extra administration work for our organisation. It may be that, in the future, EU directives would need to be altered in order to make GMM technologies like ours more easily available for public benefit. Deliberate release regulations already contain a separate section for commercial use, and contained use may be separated this way in the future too.

For class 1 organisms, no further notification is needed before commencing with contained use (Article 7). For higher risk classes more information is needed; as our organism is only class 1 we will not consider this, but rules can be found in Articles 8 and 9.

Further thought should be given to the minimum containment measures stipulated in Annex IV, and whether our system meets these conditions. There are different requirements given for different potential situations. Our proposition would most likely fall under “Containment and other protective measures for other activities” for the panel itself, but other containment procedures would need to be reviewed for labs where genetic modification is done and areas where GMMs are cultured. Almost all containment options for class 1 organisms in this category are optional according the Annex IV. It is likely that the level of containment assumed for this category is more severe than in our proposition (i.e. the EC has assumed all contained use will occur inside a building). As such, we should expect to see some or all of the containment measures to be required, rather than optional, for our project.

Beyond the obvious physical containment, there are several possible containment measures we could be required to enforce. This includes control of aerosols during “addition of material to a closed system or transfer of material to another system”. This would include transferring cyanobacteria to the fuel cell, which would be done in a separate contained facility, and during the removal of waste or the waste filter (see design section), which would have to be done on site. The latter is one of the biggest issues our project could face.

Inactivation of waste containing GMMs is also listed as optional, but could potentially be required. Furthermore, the air leaving the system, assuming filter-sterilised air is bubbled through our panel, could have to be filtered to prevent or minimise release. The only point already required for class 1 work is that personnel wear protective clothing.

According to Article 13, an emergency plan is required. This must be made available to the public, relevant bodies and authorities, and other concerned EU member states. The plan is required in case containment measures fail, leading to “serious danger, whether immediate or delayed, to humans outside the premises and/or to the environment”. No information is given on how extensive this plan should be, and no minimum requirements are given. Member state legislation must therefore be consulted for any rules on how the plan must be structured.

Finally, it should be noted that member states may consult the public on the proposition if they decide it is relevant (Article 12).

EU: Deliberate Release

Below is outlined some of the salient points from the EU directive on deliberate release. These may be useful to other teams reviewing regulations. The key points are:

• a risk assessment is required (Article 4; Annex III)
• regulations are different for commercial and non-commercial use
• for non-commercial GMO work (Part B):
• parties must give a risk assessment and monitor use and effects
• the authority can tell the public
• approved uses must be reported to the EU
• for commercial GMO work (Part C):
• parties must notify the relevant authority before placing the product on the market
• putting it on the market is defined as making it available to 3rd parties
• the authority produces an “assessment report”
• this is given to the applicant, the EC and EU member states
• decisions apply throughout the EU
• the public must be notified
• as Directive name, released in x 2014, member states can restrict or ban GMOs in their country that have been approved for all states (link)

UK Regulations

Introduction to UK Regulations

The EU regulations are useful to us as they provide a baseline level of regulation we can expect if we try to implement our technology anywhere in the EU. In each EU member state, it is ultimately that country’s regulations which we must abide by. We will now consider what the regulations are like the UK.

In general, they are slightly stricter than the basic EU regulations. The main regulations are the HSE Contained Use regulations (link), which are newly updated for 2014, and the accompanying SACGM Compendium of Guidance, which has yet to be updated to meet the new Contained Use document. Along with this, there are the regulations on deliberate release (link) from 1997, section 108(1) of the Environment Protection Act (link) from 1990, and the Genetically Modified Organisms Regulations (1996, link) that are related to GMOs. The latter three are all focussed on environmental release, so won’t be covered here. Regulations are upheld by the HSE and DEFRA. The HSE website can be consulted for all other regulations that might relate to the use of GMOs (link).

UK Regulations: Contained Use

The essential requirements for contained use in the UK are in the line with EU rules; we need to carry out a risk assessment and classify our organism, and notify the HSE before commencing GM work. So far we have only talked about the sites where the panels will be installed, but we will also have to consider regulations for handling, transport, work area decontamination, inactivation of GMMs and their disposal (including waste management). While the GMMs’ safety would need to be assessed by HSE, the system containing them, our panel, will need to be tested for leakages, with this evidence submitted to DEFRA.

The definition given for contained use in Part 1, regulation 2 is “an activity in which organisms are genetically modified or in which genetically modified organisms are cultured, stored, transported, destroyed, disposed of or used in any other way and for which physical, chemical or biological barriers, or any combination of such barriers, are used to limit their contact with, and to provide a high level of protection for, humans and the environment”. Also in part 1, regulations 26 specifically tells us that commercial disposal of waste containing GMOs also falls under contained use. The contained use definition is similar to the EU definition, but is slightly more specific about what the containment measures must entail. In Part 1, paragraphs 24 and 45 give examples of what the barriers for our system might be expected to be. Physical could include a container, which would be the panel itself in our case. Chemical barriers may cover inactivation before waste disposal, and biological would include attenuating characteristics that debilitate the organism so that it is “rendered unable to survive outside of a specialised environment”. These barriers are discussed further in the safety page (link).

The first requirement to consider is the risk assessment. For GMMs this is covered in Part 2, regulation 5, with more details on the assessment in Schedule 3 (Part 2). More emphasis is placed on risk to human and health and environment than in EU regulations. Regulation 5, paragraph 43, also answers questions we raised in the “EU: Contained Use” section about whether we could apply the same risk assessment to multiple sites with the same roof installation: “Where the contained use is identical at the multiple sites (eg in a clinical trial), the same risk assessment may apply to all the sites”. However it does point out that local changes in practices need to be taken into account. For us, practices would remain the same, but the surrounding environment may be different (e.g. there may be a pond at one property, where our organisms could theoretically survive). What the risk assessment must encompass is introduced in paragraph 44. In short, we must outline our plans, potential harmful effects, the chance of them occurring and their severity, and how we’ll deal with waste. These topics are covered in the safety page (link), where we look at each of our mutations; waste disposal is covered in the Fuel Cell page (link).

It is clear that the detail needed in the risk assessment is partly defined by how well-understood the microorganism and mutations are. Although our organism is clearly a non-pathogenic, non-hazardous class 1 organism, it is not as well understood as Escherichia coli K-12, for example, and the genes are not ones that are commonly used. They do not have a strong history of safe use, like green fluorescent protein (GFP). All our mutations have been done before, however, while measuring for different endpoints, so literature is available for reference on the effects of our mutations. From paragraphs 52 and 53, we know that the classification of the work changes to reflect the level of containment needed. When considering EU regulations, we were unsure of the extent of containment required, as our organism is class 1, but is used in unusual and potentially problematic environments. Under UK regulations, it appears our work could be reclassified to class 2 if we deem the containment measures for class 2 work to be desirable. This brings in a previously unforeseen hurdle: our work may be relabelled as higher than class 1 because of the containment measures needed on private properties with no trained personnel. We will continue to assume our work is class 1, but mention class 2 rules where appropriate.

In summary, for the risk assessment we must identify hazards, assign appropriate containment measures, then reclassify our work based on these (if necessary). These instructions are similar to, but more detailed than, those for EU member states in general.

According to regulation 8, we need to obtain advice from a person or committee on the risk assessment. If our organism were reclassified as class 2, this would have to be a biological safety committee. At Reading this would not be an issue, as there is already a committee from which we could obtain advice. If the classification remained as class 1, our meeting with Gretta Roberts and Professor Jim Dunwell, who have advised us with regards to regulations and safety, should be sufficient.

Regulation 9 requires notification of premises to be employed for contained use. We must first submit the information in Schedule 5, then wait 10 days for a response. A single notification may include more than 1 premises in situations where more than one premise is owned by the same company, so it’s possible that multiple sites could be asked about at once. This would reduce the cost of notifying HSE, which is currently £472 for class 1 and £943 for class 2. However, if our organism still falls under class 1, we only need to submit a summary of the risk assessment, details on waste management and the advice we received during the risk assessment, and confirmation that relevant authorities will be notified of the emergency plan. The rest of the information needed is basic details like the address of the premises. For class 2 work, regulation 10 should be consulted.

Part 3 outlines practices that must occur for contained use. Regulations 18, 19, 21 and 22 are all relevant to different stages of our plans. Sections relevant specifically to the panels include paragraphs 107-109, which tell us that containment measures must be tested; this may involve checking each panel for defects or leaking before deployment, and possibly visiting sites at intervals to check they are still functioning correctly (paragraph 108). This could mean simply looking over the panel for any cracks or leakages to check for physical containment. Checking that biological containment is still in place, for example by checking that cells cannot directly transfer or uptake DNA after the pilT1 mutation (see safety), may involve taking a sample from panels. This itself means removing liquid containing GMMs and transporting it back to the lab for testing transformation efficiency; we would have to ensure that taking any liquid samples would not have any risks of accidental release. It is unlikely, but possible, that we could be required to check for our GMM in the surrounding environment to ensure there had been no release (paragraph 111). This is covered by the safety page, on testing the environment for our organism (link).

Regulation 19 specifically covers containment measures for GMMs. Containment measures must be reviewed “at regular intervals” (paragraphs 128 and 129), which must occur more frequently for non-standard work. According to paragraph 134, our organism does not fit the criteria for class 1 work that does not require waste inactivation, because our organism does not contain “multiple disabling mutations”, so waste from our panel must be inactivated. According to 135, it is acceptable to take the filter to another location and autoclave it, assuming steps are taken to make sure storage and transport are safe, and that the process is effective at inactivating our GMM.

We must follow Schedule 8, Part 2, Table 2 for containment measures. As with our assessment of EU containment requirements, we have chosen the “other” section, as this seems most appropriate. Here the only absolute requirement is that personnel must wear work clothing. Measures that might be required, if deemed so by the risk assessment, include: physical separation, control of aerosols (as discussed in the EU contained use section), inactivation of waste or removed fluid, and control for spillage. The last of these is the only one not fully considered so far in our design.

Emergency plans are discussed in regulation 21. According to paragraph 139, however, “an emergency plan should only be prepared for work with organisms that pose the highest hazards to humans or the environment.” Although our organism is low hazard, the risk is perhaps higher because the GMMs are not contained in a facility. As only hazard is mentioned, it is possible that we would not have to draw up an emergency plan (for our organism the hazard is low, but the risk slightly higher as it is not contained in a building). Furthermore, only those on the premises would be exposed to our non-dangerous GMM, but paragraph 139 only requires an emergency plan when the health or safety of those outside the premises is in danger. This probably assumes the work is a designated building with trained personnel on site, though. Given this, and our non-standard plans, it would be prudent to anticipate an emergency plan being required. If this were the case, it must be submitted along with our contained used application to HSE (paragraph 140). Paragraph 141 covers the requirement for an emergency plan; those “on the site affected by the plan” should know the plan, so residents in houses where a panel is installed, or building managers for a university building, would have to be familiar with the plan (paragraph 142). The plan must also be publicly available (paragraph 143), as we know from the EU requirements. Although we have primarily talked about the risk to the environment of our GMMs, we should also consider the risks of releasing potassium ferricyanide to the environment (a part of our solar panel), like how much would be released, any risks to human health or safety, and any risks to the environment.

Other Regulations

We’ve covered the main EU and UK regulations regarding the installation of our actual panels, but there are many other regulations relevant to our plans. Contained use regulations are the main ones, which would cover the genetic modification of our organisms in a lab, the transport of our organisms to a facility where they can be grown up, that facility itself, transport to houses or the university, and the property where the panel is installed. There are other regulations that could come into play, however. This includes rules on the carriage of dangerous goods, which might include our GMMs or potassium ferricyanide. Furthermore, transport regulations for crossing borders in the EU, which might occur if we export cultivation of our GMMs to another country, would mean we must adhere to EU GMO border rules in Regulation EC 1946/2003, which implements the Cartagena Protocol.

We’ve covered the main EU and UK regulations regarding the installation of our actual panels, but there are many other regulations relevant to our plans. Contained use regulations are the main ones, which would cover the genetic modification of our organisms in a lab, the transport of our organisms to a facility where they can be grown up, that facility itself, transport to houses or the university, and the property where the panel is installed. There are other regulations that could come into play, however. This includes rules on the carriage of dangerous goods, which might include our GMMs or potassium ferricyanide. Furthermore, transport regulations for crossing borders in the EU, which might occur if we export cultivation of our GMMs to another country, would mean we must adhere to EU GMO border rules in Regulation EC 1946/2003, which implements the Cartagena Protocol.

We’ve covered the main EU and UK regulations regarding the installation of our actual panels, but there are many other regulations relevant to our plans. Contained use regulations are the main ones, which would cover the genetic modification of our organisms in a lab, the transport of our organisms to a facility where they can be grown up, that facility itself, transport to houses or the university, and the property where the panel is installed. There are other regulations that could come into play, however. This includes rules on the carriage of dangerous goods, which might include our GMMs or potassium ferricyanide. Furthermore, transport regulations for crossing borders in the EU, which might occur if we export cultivation of our GMMs to another country, would mean we must adhere to EU GMO border rules in Regulation EC 1946/2003, which implements the Cartagena Protocol.

Findings and Conclusions

Meeting experts in GMO safety and regulations, and consulting the appropriate legislation, has brought a number of key findings to light. Perhaps the most interesting is that current rules are not set up to cover a project like ours, that involves a container of GMMs outside and building, possibly on a person’s private property. As the Scientific Committees that in the EC are currently reviewing the risks of synthetic biology, and that GMO-devices may become more common in the future, we may see regulations adapting more to cover these areas in the coming years.

Although there are clearly areas where our panel counts as non-standard use, and so might be reclassified as higher risk than class 1, passing regulations may not be our biggest hurdle in getting our technology to the market. Our system complies with the safety measures needed, and our organism is of no or negligible risk to human safety or health, or the environment. Other obstacles that might be difficult to pass include how heavy our panels will be, and whether this will be a problem for transport or installing on rooftops, as having employees or members of the public on roofs would be a large safety risk in itself. The cost of submitting contained use applications to HSE also needs to be taken into account, and how the panels will be maintained without trained personnel on site. Furthermore, aspects of scaling up our technology also need to be worked out, such as what the optimal ratio of cyanobacteria-inoculated media to potassium ferricyanide is, and whether our cyanobacteria will survive long-term use in a photovoltaic cell. In addition, we do not know if people will be interested in continuing to pay for new media that must be added. By contrast, normal photovoltaic cells are one-off payments, even if they would be much more expensive than a cyanobacterial photovoltaic cell.

The Roadmap

This is a bullet-point guide of what we’d need to do, step-by-step, to get our product to the market. It also provides a summary of our findings. It is by no means exhaustive though. We have focussed on the panels, rather than other aspects of our hypothetical business, and expect that many hurdles would magically appear to make life more difficult if we attempted to carry out our proposal.

• Get proof that our organisms our less fit (competition assay)
• Get proof that our system is secure (leaks)
• Carry out a risk assessment
• Get advice from an expert person or panel on the risk assessment
• Provide appropriate containment measures
• Review the class of our work in respect to the containment measures
• Draw up an emergency plan, inform the relevant personnel.
• Submit an application to HSE, pay £452 for each site
• Wait 10 days for acknowledgement of receipt
• Commence work

Before any of this, it would be advisable to contact HSE to for advice on our proposition, however.

Resources

In this report we mainly referred to a few pieces of legislation, conversations we had with experts, and other sections of our wiki. As such, it made a lot more sense to link to all our resources as we went along, rather than using a Harvard or Vancouver style of referencing. However, we realise that it’s also convenient to have all the resources or references in one section. Here is a list of resources we used. If you’re hoping to review regulations on GMMs in the EU, this should be your starting point.

Worldwide

The Cartagena Protocol - UN-ratifed agreement for transborder GMO movement

EU Directives

Directive 2009/41/EC - contained use
Directive 2001/18/EC - deliberate release
Directive 2000/54/EC - risk classification of organisms
Regulation EC 1946/2003 - transborder movement of GMOs. Implements the Cartagena Protocol
Opinion on Synthetic Biology - first in a series to start reviewing risk in synthetic biology
For other EU legislation, start here

UK Regulations

Contained Use
SACGM Compendium of Guidance
Other UK rules are mentioned here

Other

We also found the BioFuel Policy Watch blog and its associated blog to be useful for general information. David Glass’s blog post on EU regulations for algae and cyanobacteria is also a great starting point.

Acknowledgements

When we first asked the question, “can we put our bacteria on a roof?”, we didn’t envision giving such a detailed response. The proposition only reached its current form through repeated rounds of meetings with the students and supervisors, time spent reading EU and UK regulations and, most importantly, meetings with experts in biosafety at Reading. Gretta Roberts and Professor Jim Dunwell were very kind in giving up their time to answer all our questions, and we are very grateful for their input.

Facebook

Twitter

rusynbioigem@gmail.com