Laws Governing Synthetic Biology

UK and EU Law

Synthetic biology has potential to help solve diverse problems and make the world a better place. This has been reflected by the eagerness of governments across the world to support and fund synthetic biology projects and initiatives.

However, the effects of genetic engineering are complex and currently difficult to predict. There is a risk that modified genes pass from our engineered organisms into wild strains, and out of our control; in plants through interbreeding, in bacteria through horizontal gene transfer. It has been mooted that genetically modified organisms may outcompete native species, reducing biodiversity, or that eating genetically modified crops may have long term adverse health effects, although there is currently little evidence for this.

The above concerns, coupled with worries from the public ranging from the ‘unnaturalness’ of genetic engineering to valid ethical and economic worries (as covered in our ethics section) have led to stringent regulations on the cultivation and release, whether controlled or into the environment, of genetically modified organisms.

In most countries, research groups/universities have committees for the approval of experiments using or producing genetically modified organisms. Higher risk experiments usually have to be ratified by a national regulatory body. In the UK, this is DEFRA, and in the U.S. the Coordinated Framework for the Regulation of Biotechnology. European assessments for approval are solely concerned with safety, whilst U.S. also considers the potential economic impact of the proposed experiments. The 6 steps in environmental risk assessment that must be followed before experimentation can take place in Europe are:

1. Identification of characteristics which may cause adverse effects
2. Evaluation of the potential consequences of each adverse effect, if it occurs
3. Evaluation of the likelihood of the occurrence of each identified potential adverse effect
4. Estimation of the risk posed by each identified characteristic of the GMO(s)
5. Application of management strategies for risks from the deliberate release or marketing of GMO(s)
6. Determination of the overall risk of the GMO(s)

It should be noted that there are various exempt dealings for laboratory based experiments on highly studied genetically modified organisms. The vast majority of iGEM projects will fit within this category- our project for one did not need to be certified by DEFRA.

As can be seen in the flowchart below, experiments with the aim of releasing the modified organisms are treated differently to those which merely aim to use the organism within a contained system. Note that this need not necessarily be in a research lab, but could be in a sealed vial.

European laws regarding the release of genetically modified organisms are notably stringent, with all organisms subject to extensive case by case evaluations by the European Food Safety Authority, and then passed through a number of other EU committees before being authorized for use.

US and Canadian Law

Our Project

Whilst the L-forms we have created with our ‘switch’ BioBrick could not currently be released into the environment under EU and UK laws- extensive testing would need to be done and our BioBrick contains an antibiotic resistance marker (which cannot be released into the environment)- L-forms of many species occur naturally. These bacteria are ‘natural’ L-forms.

Part of our project involves the fusing of L-forms to promote genome shuffling and directed evolution. Would the fusion of two natural L-forms constitute genetic engineering? In theory, fusion could occur very rarely naturally. Arguably our project is very similar to fertilization, with two cells fusing and similar genomes mixing. It is also similar to meiosis, with genome shuffling nearly indistinguishable from crossing over. In which case, could L-forms that have undergone rounds of genome shuffling count as genetically engineered?

UK law appears clear on this. The following is cited as an example of genetic modification:

cell fusion or hybridization techniques where live cells with new combinations of heritable genetic material are formed through the fusion of two or more cells by means of methods that do not occur naturally.

However are the methods by which we are inducing fusion unnatural? On one hand, we are physically pushing the L-forms together, and PEG is required to put shear stress of the cell membranes. But fusion can occur naturally in L-forms. Furthermore whilst the legislation is fairly clear, there have been no cases yet, and so it is not fully clear how the laws should be interpreted, or whether the legislation has any wiggle room or could be challenged.

Cells that have undergone genomic fusion are exempt from many of the regulations that other genetically modified organisms are subject to, as stated in ‘The Genetically Modified Organisms (Contained Use) Regulations 2000’. This would be useful for researchers hoping to use L-forms for directed evolution. It should be noted however that random mutagenesis is also exempt from all but regulation 17, as can be found [here].

Defining GMOs

Definition of GMOs in UK legislation Regulations 2(1) and 3(2)

PART I

EXAMPLES OF TECHNIQUES CONSTITUTING GENETIC MODIFICATION

1. Examples of the techniques which constitute genetic modification which are referred to in sub-paragraph (a) of the definition of “genetic modification” in regulation 2(1) are- (a) recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules, produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation; (b) techniques involving the direct introduction into an organism of heritable genetic material prepared outside the organism, including micro-injection, macro-injection and micro-encapsulation; (c) cell fusion or hybridization techniques where live cells with new combinations of heritable genetic material are formed through the fusion of two or more cells by means of methods that do not occur naturally.

PART II TECHNIQUES WHICH ARE NOT CONSIDERED TO RESULT IN GENETIC MODIFICATION 2. The following techniques are not considered to result in genetic modification provided that they do not involve the use of genetically modified organisms made by techniques other than those listed in Part III or the use of recombinant nucleic acid molecules, namely— (a) in vitro fertilisation; (b) natural processes including conjugation, transduction or transformation; (c) polyploidy induction.

Definition of GMOs in EU legislation

Article 2(b) of EU Directive 2009/41/EC on the contained use of genetically modified micro-organisms ‘Genetically modified micro-organism’ (GMM) means a micro-organism in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination; within the terms of this definition:

1. genetic modification occurs at least through the use of the techniques listed in Annex I, Part A;
2. the techniques listed in Annex I, Part B, are not considered to result in genetic modification;

Annex 1- Part A Techniques of genetic modification referred to in point (b)(i) of Article 2 are, inter alia:

1. Recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation.

2. Techniques involving the direct introduction into a micro-organism of heritable material prepared outside the micro-organism, including micro-injection, macro-injection and micro-encapsulation.

3. Cell fusion or hybridisation techniques where live cells with new combinations of heritable genetic material are formed through the fusion of two or more cells by means of methods that do not occur naturally.

Annex 1-

Part B Techniques referred to in point (b) (ii) of Article 2 which are not considered to result in genetic modification, on condition that they do not involve the use of recombinant-nucleic acid molecules or GMMs made by techniques/methods other than the techniques/methods excluded by Part A of

Annex II:

1. in vitro fertilisation; 2. natural processes such as: conjugation, transduction, transformation; 3. polyploidy induction

Article 2(2) of EU Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms: “Genetically modified organism (GMO)” means an organism, with the exception of human beings, in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination; Within the terms of this definition: (a) genetic modification occurs at least through the use of the techniques listed in Annex I A, part 1; (b) the techniques listed in Annex I A, part 2, are not considered to result in genetic modification;

Annex I A - Part 1 Techniques of genetic modification referred to in Article 2(2)(a) are inter alia:

(1) recombinant nucleic acid techniques involving the formation of new combinations of genetic material by the insertion of nucleic acid molecules produced by whatever means outside an organism, into any virus, bacterial plasmid or other vector system and their incorporation into a host organism in which they do not naturally occur but in which they are capable of continued propagation; (2) techniques involving the direct introduction into an organism of heritable material prepared outside the organism including micro-injection, macro-injection and micro-encapsulation; (3) cell fusion (including protoplast fusion) or hybridisation techniques where live cells with new combinations of heritable genetic material are formed through the fusion of two or more cells by means of methods that do not occur naturally.

Annex I A - Part 2 Techniques referred to in Article 2(2)(b) which are not considered to result in genetic modification, on condition that they do not involve the use of recombinant nucleic acid molecules or genetically modified organisms made by techniques/methods other than those excluded by Annex I B: (1) in vitro fertilisation, (2) natural processes such as: conjugation, transduction, transformation, (3) polyploidy induction

References