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12    | December 2010 | Realising European potential in synthetic biology 

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characterisation of Mycoplasma pneumoniae (footnote 

10) as a potential chassis for importing novel biological 

functions through synthetic biology may bring new 

therapeutic applications within range.

There is a rapidly growing database of synthetic 

building blocks (DNA sequences of defi ned structure 

and function). Signifi cant impetus in this area has been 

provided by the Massachusetts Institute of Technology 

(MIT) initiative to develop a standard registry of biological 

parts (BioBricks

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) and to host an international student 

competition (International Genetically Engineered 

Machine Competition, iGEM), where participants design 

new systems based on BioBricks.

The research area of minimal genomes may lead to many 

new utilities. One application currently being pursued 

is the design of novel microbes to produce hydrogen or 

other biofuels

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. Other, still limited, experimental data 

discussed in the Berlin meeting (Appendix 1) show that 

some reduced genomes are more productive in certain 

respects (for example amino-acid synthesis), potentially 

supporting various other applications in industrial 

production.

5.2  

Orthogonal biosystems: expanding the 

genetic code

As an alternative approach, new properties of cells 

might be engineered to expand information storage 

by adding coding capacity—for example, by building a 

parallel protein translation capability within the cell. The 

strategy associated with orthogonality aims to modify 

subsystems without causing signifi cant disturbance 

elsewhere. Several routes have been proposed for 

engineering the genetic code to incorporate artifi cial 

amino acids. One approach, pioneered in the USA 

and UK over the past decade, is to create ribosomes 

(nucleic-acid-dependent amino-acid polymerases) 

with expanded chemical scope to act as novel cellular 

translation systems able to synthesise unnatural proteins. 

Control over macromolecular interactions exerted by 

this parallel modular synthesis requires orthogonal 

ribosome/messenger RNA (mRNA) pairs (the latter 

generated by the unique aminoacylation of transfer 

RNA (tRNA) with unnatural monomers). The artifi cial 

proteins can be synthesised with high effi ciency (Wang 

et al. 2007), bringing various applications in vivo within 

range. For example, it will be possible to incorporate 

specifi c functionality in order to study the topology of 

protein interactions in systems that have been hard to 

characterise hitherto (within biological membranes) 

and to encode specifi c post-translational modifi cations, 

creating homogenous protein therapeutics (such as 

polyethylene glycol-derivatised proteins to improve 

pharmacokinetics)

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.

An alternative and complementary approach is based 

on propagating in vivo additional types of nucleic acids 

(xeno-nucleic acids, XNA), whose chemical backbone 

differs from deoxyribose and ribose (Herdewijn and 

Marliere 2009; Marliere 2009). XNA building blocks 

would not be found in nature but can be supplied 

exogenously to cells that would also have to be equipped 

with the additional, appropriate, enzyme machinery for 

replicating and expressing XNA. This would result in the 

establishment of a genetic enclave unable to exchange 

genetic information with the natural nucleic acids. 

First steps in this endeavour are being explored in the 

Framework Programme 7 Orthosome project.

As discussed in the German Statement on synthetic 

biology compiled by the academies together with the 

major research funder, DFG (DFG, German Academy 

of Sciences Leopoldina and Acatech 2009), orthogonal 

biosystems offer a generalisable way of increasing 

biological safety because an artifi cial genetic code can 

only be translated in organisms with the respective 

orthogonal translation system.

5.3 Regulatory 

circuits

Novel cellular function is a matter not just of molecular 

chemistry but also of circuitry. Synthetic gene circuits 

that emulate the expression dynamics of living systems, 

and are perceived as analogous to electronic circuits, are 

beginning to provide new insight into complex control 

networks. Although there is no clear boundary between 

classical biotechnology and synthetic biology with respect 

to the development of artifi cial circuits, recent work has 

led to the regulation of post-transcriptional mechanisms 

as well as transcriptional control.

Artifi cial gene networks can be designed from modular, 

well-characterised and compatible genetic components, 

such as molecular switches and biological memory, 

implanted into natural systems. For example, the work 

of Fussenegger and colleagues in Switzerland, part-

funded by Framework Programmes, produced a synthetic 

mammalian oscillator based on an auto-regulated, 

sense-antisense transcription control circuit, that enables 

autonomous, self-sustained and tuneable oscillatory gene 

expression (Tigges et al. 2009). Earlier work by this group 

described a range of new tools for circuitry; including 

gas-inducible transcription control in a heterologous 

system (Weber at al. 2004) and a synthetic time-delay 

circuit in mammalian cells (Weber et al. 2007b). Even 

more ambitiously, a synthetic ecosystem (interconnection 

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http://parts.mit.edu.

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International patent applications were fi led by the Craig Venter Institute in 2007.

14 

www.ambrx.com.

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