EASAC
Realising European potential in synthetic biology | December 2010 | 9
The fi rst product class to emerge is likely to have a
major infl uence on public expectations. From a policy
perspective, what is perhaps more important than the
short-term predictions of specifi c product outputs is
the need to build the R&D infrastructure and culture
for the longer-term to underpin the emergence of
multiple applications, including those that are presently
unanticipated.
A recent survey of public perceptions commissioned by
the Royal Academy of Engineering in the UK
7
showed
that awareness of synthetic biology is low but that, when
information is provided, members of the general public
expressed great interest in the prospect of designing
microorganisms to help manufacture biofuels and
medicines. Concern was expressed, however, about
deliberately releasing artifi cial organisms into the
environment to tackle pollution. Public respondents
wanted government to regulate synthetic biology
but were concerned that regulation should not stifl e
development of the area. Public views on patenting were
mixed but there was understanding that investors are
entitled to a return on their time and money, within the
broader context of balancing returns on investment and
social responsibility.
It is important for this work on public attitudes to be
extended across the EU; there has already been some
examination of societal attitudes in work funded by
the European Commission (Appendix 2) and there is an
Austrian study in progress
8
.
7
‘Synthetic Biology: public dialogue on synthetic biology’, The Royal Academy of Engineering, June 2009, at www.raeng.org.
uk/news/publications/list/reports/Syn_bio_dialogue_report.pdf . This public dialogue was held to complement the Academy’s
inquiry, published in May 2009, ‘Synthetic biology: scope applications and implications’, at www.raeng.org.uk/synbio.
8
“COSY – Communicating Synthetic Biology”, at www.idialog.eu/index.php?page=cosy. Further information on this study and
other societal aspects of synthetic biology was published in a special issue of the journal Systems and Synthetic Biology (Schmidt
2009).
4
Public expectations of synthetic biology research and
applications
EASAC
Realising European potential in synthetic biology | December 2010 | 11
‘The synthesis of increasingly complex unnatural net-
works embedded in living matter is an emerging theme in
synthetic biology’ (Chin 2006). Such achievements have
become possible because of the major improvements in
the precision, speed and cost reduction in gene sequenc-
ing and DNA synthesis, coupled with the techniques of
gene transplantation, genome assembly, model building
and computational design.
Synthetic networks have enabled the generation
of systems endowed with genetic components and
expanded genetic code (see section 5.2). Broadly, there
are two approaches to doing this: involving either the
assembly of well-characterised, freely combinable,
naturally occurring modules
9
into novel networks or the
creation of unnatural, standardised modules. Although
the experimental approaches may vary widely, the
common challenge is to exert the necessary molecular
control in time and space to achieve the desired outcome.
As Chin (2006) observes, endowing living organisms
with new functions can be diffi cult for several reasons—
they are complex, open systems that operate far from
thermodynamic equilibrium, there is lack of information
on the cell-wide specifi city of molecular interactions, and
components in vivo are much harder to defi ne and control
than in vitro. Despite these challenges, signifi cant success
has been achieved in demonstrating the novel techniques.
Advances are also being made towards the objective of
creating artifi cial cells de novo. Where possible, examples
of research taking place in Europe are described in the
following sections, but areas where Europe is lagging
behind the USA are also highlighted. The examples
have been chosen to illustrate key points rather than to
be a comprehensive account of the fi eld and to cover
approaches in vivo (sections 5.1–5.4) and in vitro
(sections 5.5–5.6). The in vitro systems are, as yet, limited
in relying on self-assembly but offer additional possibilities
to sample the ‘chemical space’.
5.1 Minimal
genomes
This is a major research area, initiated in the USA, to
defi ne the minimal number of parts (genes) needed for
life, based on a full description of those parts and their
interaction, to serve as a basis for engineering minimal
cell factories for new functions. Such work builds on
advances in several areas of genomics and related
disciplines—the use of comparative genomics approaches
to identify shared core genome sequences across species;
systematic gene disruption studies to explore function;
the characterisation of naturally evolved minimal gene
sets (for example in parasites or endosymbionts for
survival in specialised environments); and the systems
biology-based computational approach. Combining the
insight gained from these research methodologies helps
to identify an obligatory set of bacterial genes for survival
in defi ned laboratory settings, with more genes required
to survive in natural environments
10
. However, the size of
this minimum gene set is still controversial. An estimate of
500–800 genes was made based on detailed analysis (Pal
et al. 2006; Feher et al. 2007) but subsequent work based
on gene essentiality studies (which may underestimate
the number of genes needed for independent life)
indicates a range of 300–400 genes.
Based on the accumulating understanding of these
minimal gene sets, the experimental approaches that
can then be taken to construct the minimal genome
can be described either as bottom-up, that is de novo
synthesis, or top-down. The latter process involves
stepwise reduction of different bacterial and eukaryotic
genomes (e.g. E. coli, Bacillus subtilis, Saccharomyces
cerevisiae, Cornebacterium glutamicum, Aspergillus
oryzae) to a reduced gene set that allows them to
function. It is noteworthy that the systematic deletion
of mobile genetic elements (e.g. insertion elements,
transposons and prophages) can increase genome
stability (Posfai et al. 2006); this may be important for
technical applications and for the construction of safe
strains.
In a scientifi c breakthrough, bottom-up work was
pioneered by researchers at the Craig Venter Institute
(Gibson et al. 2008) synthesising the Mycoplasma
genitalium genome
11
. This organism, with a small
genome and minimal metabolic complexity, may become
a platform for understanding how the simplest cell
works. Assessing the resilience of such minimal cells, in
particular how they behave under stressful conditions
or in an industrial setting, represents an important
topic for future research. The bottom-up approach has
potential advantages in fl exibility of design and rapidity of
construction, but relies on improvements in speed of DNA
synthesis and genome transplantation. The top-down
alternative is perhaps more controllable but the genetic
tools are not yet available for many species. The greatest
opportunity may reside in merging the approaches,
where a modular core genome serves as a chassis for
replacement by synthesised elements. For example, the
9
A module is defi ned as a collection of molecules whose function can be perceived as discrete.
10
Other research funded by the Sixth and Seventh Framework Programmes (3D-REPERTOIRE and PROSPECTS respectively)
provides detailed information on the cellular machinery required for Mycoplasma pneumoniae to survive independently
(Kuhner et al. 2009).
11
In the period since the Working Group fi nalised their drafting of the EASAC report, this scientifi c team has made further very
signifi cant accomplishments in synthetic biology (see footnote 1 in the Foreword to this report).
5 Methodological approaches in synthetic biology