Easac'10 sb indd

EASAC 

Realising European potential in synthetic biology | December 2010 |    13

of bacterial, yeast and mammalian cell signalling) that 

begins to mimic fundamental coexistence patterns in 

nature such as symbiosis and parasitism, involved the 

engineering of sender cells to transmit volatile molecules 

to recipient cells to induce their expression of target genes 

(Weber et al. 2007a). It is also envisaged that prosthetic 

gene-network devices can be integrated into cells and 

functionally connected to their metabolism in order to 

sense and correct metabolic disturbances, by triggering 

a self-suffi cient therapeutic response. Proof-of-principle 

was demonstrated recently in a model system whereby 

homeostasis of urate (elevated in tumour lysis syndrome 

and gout) was maintained in the mouse bloodstream 

(Kemmer et al. 2010).

Other European research is combining the techniques of 

synthetic biology and systems biology to design new in 

vivo functions. For example, a synthetic network in yeast, 

comprising fi ve genes regulating one another in multiple 

ways, provides a test-bed for benchmarking reverse 

engineering and modelling (Cantone et al. 2009).

These examples can be seen as constituting the fi rst 

steps towards interconnecting basic modules in complex 

systems. There are still obstacles to translating the 

fi ndings: the artifi cial circuits are integrated within 

a biological system that is not itself well understood 

and the new components are subjected to the host 

organism’s complexity. Unintended interactions between 

the synthetic circuit and cell physiology can infl uence 

circuit function and their interplay can only be predicted 

to a limited extent and must, therefore, be assessed 

empirically. Nonetheless, these research advances 

are enabling the understanding of structure-function 

correlation in cellular signal process circuitries and may 

engender various novel applications, for example in 

gene therapy, tissue engineering and biopharmaceutical 

manufacturing. As a basic safety principle, it is prudent 

to ensure that the functioning of artifi cial gene circuits 

depends on exogenously applied inducers.

A recent review of other developments (Kiel et al. 

2010) compared the current situation for engineering 

genetic circuits with the longer-term opportunities 

and challenges for engineering signal transduction 

pathways in prokaryotic and eukaryotic cells. Whether 

signal transduction pathway engineering can become 

a discipline analogous to DNA engineering depends 

to a signifi cant extent on the generation of reliable 

standardised parts. Although crosstalk between synthetic 

and native elements does not appear to be so signifi cant 

a problem as originally feared, a continuing lack of 

understanding about negative feedback regulation could 

be problematic if such regulation dampens signalling 

outcomes in engineered systems (Kiel et al. 2010).

More broadly, the manipulation of circuits in cells and 

other methodologies in synthetic biology will be facilitated 

by developments in other technology platforms, for 

example micro-fl uidics (Gulati et al. 2009). Micro-fl uidics 

offers the prospect of working with smaller reagent 

volumes, shorter reaction times and in parallel operations 

enabling, for example, integration as the ‘lab-on-a-chip’.

5.4 Metabolic 

engineering

One signifi cant development in synthetic biology is 

the engineering of modifi ed biosynthetic pathways to 

produce useful materials that they do not produce in their 

wild-type form, building on a relatively long tradition 

of using genomic technologies to produce increased 

quantities of natural products

15

. The most frequently 

quoted synthetic biology example is the production in 

yeast and E. coli of artemisinic acid, a precursor of the 

isoprenoid artemisinin, an anti-malarial drug traditionally 

obtained, in inadequate amounts, from the plant 

Artemisia annua. It was predicted that artemisinin derived 

from yeast, potentially reducing production costs by 

90%, could be marketed within two years

16

. Other recent 

examples of metabolic engineering include the following:

•   Production of the anti-cancer drug taxol in 

S. cerevisiae.

•   Production of a precursor of spider silk in Salmonella 

typhimurium, capitalising on the ability of the 

pathogen to secrete the protein (which is toxic to 

cells).

•   Second-generation biofuels, for example engineering 

yeast to catabolise C

5

 sugars (xylose) as well as 

C

6

 sugars (glucose).

•   Genetically modifying a plant virus with additional 

lipase activity to create a biocatalyst with 

programmed self-assembly and reproduction (Carette 

et al. 2007), thereby providing proof-of-principle for 

a cascade catalytic system operating like a metabolic 

pathway.

•   Synthesis of hydrocortisone from glucose in yeast.

The question remains as to the extent that the current 

examples illustrate novel attributes of synthetic biology 

or can be regarded instead as an extension of previous 

research in genetic engineering. What is clear is that 

examples are appearing that increasingly represent more 

complex biological systems embodying the application of 

engineering principles in rational design and capitalising 

on the standardisation of predictable modular biological 

components, based on detailed understanding of the 

15  

For example, the improvement of strains of actinomycete bacteria to alter the regulation of the biosynthesis of antibiotics and 

their precursors (Lum et al. 2004).

16  

Press release at www.amyrisbiotech.com/pdf/Amyris_Press_Release_03_03_08.pdf. Estimates that are more recent forecast 

2012.

---