03 SYNBIO

Synthetic Biology’s Brief History

Excerpt from the Synthesis handbook

by Jane Calvert, University of  Edinburgh

iGEM 2004 UT Austin/UCSF Team. Hello World bacterial photograph. Photograph by Aaron A. Chevalier.

‘Synthetic’ is an ambiguous word since it can mean either ‘constructed’ or ‘artificial’. The former meaning is preferred by synthetic biologists, but it is inevitable that the notion of ‘artificial’ is associated with the field. In fact, attempts have been made to avoid the word ‘synthetic’ by naming the field ‘constructive biology’ or ‘intentional biology’, but these names have not become widely adopted. Apparently, molecular biologists objected to the name ‘intentional biology’ because it seemed to imply that all previous biology had been unintentional! (Carlson 2006)

History of synthetic biology

The term ‘synthetic biology’ is usually traced back to 1912 to Stéphane Leduc’s book La biologie synthétique. Leduc wanted to “assemble purely physical and chemical systems that demonstrated behaviors reminiscent of biology” (Keller 2002, p.28), and he grew crystals that resembled organic objects like flowers and mushrooms. The next direct reference to the term is found in 1974 when the Polish geneticist Waclaw Szybalski talked of a “new era of synthetic biology where not only existing genes are described and analyzed but also new gene arrangements can be constructed and evaluated” (Szybalski and Skalka 1978). The first conference called ‘Synthetic Biology’ was at MIT in 2004.

Rather than restricting ourselves to the term ‘synthetic biology’, if we think of synthetic biology as an engineering approach to life, then the historian Luis Campos (2009) points out that such an approach can be found at least as far back as the late 19th century when some biologists started to think of themselves as engineers. An example of this attitude is Loeb’s book The Mechanistic Conception of Life, published in 1912. Loeb said that his dream was “to see a constructive or engineering biology in place of a biology that is merely analytical” (quoted in Campos 2009, p.11). Campos also traces this mentality through to Jacob and Monod’s work in the 1960s which showed how genetic circuits could be engineered. But Campos also observes “a peculiar perception common among synthetic practitioners, and recurring over decades: that they alone have been the first to truly aim for – and possibly attain unto – a properly engineered biology” (p.16).

Overview of approaches

One of the immediately striking features of synthetic biology is that there is a great deal of discussion about what is and what is not synthetic biology, with competing definitions and border disputes. Most definitions of synthetic biology have two parts: the construction of completely novel biological entities, and the re-design of already existing ones

The word’s first synthetic lifeform? Image: JCVI, 2009

A simple initial way of grasping the field is to distinguish between three schools of synthetic biology, which focus on biological entities of increasing scale: the construction of standardized biological parts (normally made of DNA); the synthesis of whole genomes, including Craig Venter’s recent work; and the creation of simple ‘proto’ cells (O’Malley et al., 2008).

Parts-based approaches draw on the engineering principles of standardisation, decoupling and abstraction (Endy 2005), with the objective of developing biological components that are capable of being easily combined in a modular fashion, along the lines of ‘plug and play’ (Isaacs and Collins 2005, Brent 2004). Analogies are often drawn to Lego bricks. These synthetic biologists hope that they will succeed in making biology into an engineering discipline (Breithaupt 2006). Metabolic engineering has much in common with parts-based approaches because it sees biological systems as things to be engineered. It manipulates existing metabolic pathways to produce new products. The most well-known example of this type of synthetic biology is the construction of an artificial metabolic pathway in E. coli and yeast to produce a precursor (arteminisin) for an anti-malarial drug (Martin et al. 2003, Ro et al. 2006).

Work at the level of whole genomes involves both ‘top down’ attempts to strip excess DNA away from existing genomes to make a more efficient ‘chassis’ which, it is hoped, will form a basis for new synthetic organisms, an approach made famous by Craig Venter’s recent work (Glass et al. 2006, Gibson et al. 2010). It also includes ‘bottom up’ attempts to construct genomes from scratch, including the synthesis of viral genomes such as the polio virus (Cello et al. 2002).

Lipid Vesicles, Image: Sheref Mansy, University of Trento

Scientists working on protocells are interested in trying to recreate living cells from very simple components. This often involves inserting molecular components into lipid vesicles (Deamer 2005). These molecular components can either be synthesised from scratch, or already existing genes and enzymes can be used (Luisi et al. 2006). This school of synthetic biology, perhaps more than any other, raises the question of what it is to create life.

There are other activities going on under the heading of synthetic biology which do not fit under these three headings, such as attempts to create an alternative genetic alphabet with new nucleotides beyond the four (ATCG) found in nature (Pollack 2001).

A feature which all approaches to synthetic biology share is a deliberate multidisciplinarity. By necessity, the field brings together biologists, engineers, chemists, physicists and computer scientists. But social scientists, philosophers, ethicists, lawyers and artists and designers are also becoming involved. It appears as if the objects being studied and constructed in synthetic biology are overflowing the boundaries of existing disciplines.

Biology as engineering

The aspiration to make biology into an engineering discipline is important for followers of the parts-based approach. These synthetic biologists make a point of distinguishing their work from previous so-called genetic ‘engineering’. The distinction between synthetic biology and genetic engineering is explained by a UK synthetic biologist: “The engineering equivalent of genetic engineering is to get a bunch of concrete and steel, throw it into a river, and if you can walk across, call it a bridge”. He adds that for this reason “genetic engineering can be considered more of an artisan craft than an engineering discipline” (Elfick, 2009). It might also be beneficial for synthetic biologists to distance themselves from some of the negative perceived social implications of genetic engineering

Use of restriction enzymes in the BioBricks Assembly standard

Even among those who are keen to promote the engineering agenda, there is a recognition that engineering in biology may look rather different from engineering in other areas, because of the “interesting and challenging features of the biological substrate” (Weiss 2009, p.1073) such as complexity, noise and evolution (Agapakis and Silver 2009). The conclusion that is usually drawn from these observations is not that synthetic biologists should give up on their attempts to engineer biology, but that they should use these particular features of biology to develop new ways of doing engineering.

As synthetic biologists often point out, there are many ways in which biological systems are superior to engineered systems. Biological systems are extremely robust, they exhibit exquisite sensitivity and specificity (demonstrated by the sensitivity of the olfactory system), and they can use sunlight as an energy source (Smolke and Silver 2011). They are also good at CO2 capture and they can synthesize complex molecules using multi-step processes (Elfick 2011). Furthermore, evolution and reproduction are powerful techniques that many synthetic biologists would like to harness to their own ends.

One reason why synthetic biologists want to make biology into an engineering discipline is because they want to replicate the successes of engineering in a biological context, drawing inspiration from the technological achievements that have arisen from other branches of engineering, such as aircraft and computers (Arkin 2008). Parallels are often drawn between today’s synthetic biology and the early days of the nascent computer industry, with the intended implication that the technological revolution that synthetic biology brings will be as important as the revolution in ICTs brought about by electrical engineering (Barrett et al. 2006).

Applications

As with other types of engineering, the range of applications of synthetic biology is potentially very broad. Examples of potential applications include microbial biofuel production, bioremediation, biosensors, new drug development pathways and synthetic vaccines (Royal Academy of Engineering 2009).

Synthetic biology pioneers, such as Craig Venter and Jay Keasling, talk about how synthetic biology will contribute to a sustainable post-carbon future (e.g. Keasling and Chou 2008). The area of alternative energy production and the possibility of carbon capture have attracted considerable media attention (e.g. Highfield 2007; Service 2008). Synthetic biologists argue that all the products we currently produce using oil and its derivatives (petrol, plastics etc.) could be produced biologically in the future.

Social, political and ethical dimensions of synthetic biology

There have been 39 reports on synthetic biology and the social and ethical issues it raises since 2004 (Zhang et al. 2011). This is a huge amount of attention considering that synthetic biology is still a reasonably small field (the biggest conference has around 700 people), and it is still in its early stages.

The ‘issues’ that are almost always associated with synthetic biology are:

Biosafety (how do we prevent the accidental release of synthetic organisms into the environment

Biosecurity (what happens if people use synthetic organisms for malevolent purposes, such as bioterrorism?

Intellectual property (should synthetic biological parts be owned by private companies or be freely available for all?

Creating life (are synthetic biologists ‘playing God’?)

 

Just because these issues are most often dicussed does not mean they are necessarily the most interesting or important. There are a range of other issues which are talked about less. These include democratisation, standardization, and interdisciplinarity.

A recent example of synthetic biology which received a great deal of attention from the press was the creation of an entirely synthetic version of a natural genome by the J. Craig Venter Institute. This genome was put into a recipient cell, where it took over the function of that cell and successfully replicated (Gibson et al. 2010). The work was heralded as a landmark achievement. But since the synthetic genome had to be put into an existing cell for it to work, many commentators say that it was an exaggeration to call it the creation of life.

A notable feature of this research is that ‘watermarks’ – words which have been coded for by DNA – have been put in to the genome. These include three literary quotations (leading the comedian Charlie Brooker to call this organism ‘The world’s most pretentious bacterium’). One of the quotes is from James Joyce’s A Portrait of the Artist as a Young Man: “To live, to err, to fall, to triumph, to recreate life out of life”. What’s particularly interesting about this quotation is that the James Joyce Estate has sent the Venter Institute a “cease and desist” letter for infringing copyright. (It is not clear if copyright is infringed every time the bacteria replicates…).

This is somewhat ironic, because Venter is well known for pursuing intellectual property and his institute has filed a patent on a minimal bacterial genome, which is a stripped-down simplified genome which can be used as a basis for applications such as biofuels. This patenting activity has led some NGOs to say that Venter may become the ‘Microbesoft’ of synthetic biology, dominating the field, like Microsoft has done for computers. This patenting activity is not characteristic of the ‘open source’ ethos of parts-based approaches.

The future

Futures for synthetic biology are often portrayed as utopias or dystopias, reflecting the fact that there is a great deal of uncertainty surrounding the field. Scientists must talk about the future applications of their work in order to get funding and mobilise support. But making claims for the potential of synthetic biology as a revolutionary technology that will transform science and industry may inadvertently give rise to broader public concerns about future developments. Talking about the future is not idle speculation: work in the ‘sociology of expectations’ (Brown and Michael 2003) has shown that discussion of the future has real effects in the present. By bringing a range of different people together to think about synthetic biology from different disciplines and perspectives, we can open up the discussion about the directions that synthetic biology may take in the future

References

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