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Brick-part biology

25 Mar, 2010
The iGEM 'BioBrick' trophy

The iGEM ‘BioBrick’ trophy

The new field of synthetic biology aims to make biology controllable, predictable and designable. Mun-Keat Looi asks if you can really engineer a biological organism and hears how a unique competition for undergraduates is helping the field gather momentum.

What if you could engineer an organism to do whatever you want: produce life-saving drugs cheaply, generate energy, or detect and clear waste from a polluted lake? And what if building that organism was like constructing a model using toy bricks or piecing together an electronic circuit? Welcome to the world of synthetic biology.

“The theory is that we now know enough about biological systems to be able to start putting them together,” says Dr Gos Micklem, Director of the Cambridge Computational Biology Institute. “At that point it becomes relevant to apply engineering principles.”

The essence of synthetic biology is to make biology controllable, predictable and designable. A 2009 report from the Royal Academy of Engineering defined it as an attempt to “design and engineer biologically based parts, novel devices and systems as well as redesign existing, natural biological systems”.

By producing standard biological parts, scientists can assemble synthetic DNA circuits that produce specific functions within cells, like putting together transistors or capacitors in electronics. Through this, researchers hope to build organisms with an efficiency that promises benefits in a variety of fields.

Take drug development and production, for example. One of the biggest achievements in synthetic biology to date is the engineering of yeast cells to produce a precursor of the antimalarial drug artemisinin, which is expensive to produce when derived naturally from the plant sweet wormwood.

This landmark, by researchers at University of California, Berkeley, showed the power of synthetic biology. Because yeast is used widely in industry (for brewing, among other things), the method could be widened to an industrial scale, bringing down the cost of the drug. Moreover, because the artemisinin-producing yeast is engineered from controllable parts, it could make it easier to create new variants of the drug that can overcome resistance mechanisms in the malaria parasite.

“The standard parts approach broadens the horizons for us to use biology in different ways,” says Professor Richard Kitney, co-Director of the new Engineering and Physical Sciences Research Council Centre for Synthetic Biology and Innovation at Imperial College London. “And it is not application-specific. It can be applied to a whole range of fields, from biofuels to pharmaceuticals.”

iGEM

When you have, as Kitney puts it, a “paradigm shift in how you approach genetic engineering”, how do you explore the possibilities it offers, not to mention build a critical mass of scientists who can expand the nascent field? That’s where iGEM comes in.

Started in 2003, the International Genetically Engineered Machine competition sets university teams from all over the world a simple challenge: if you could make anything, what would you make?

“It’s the opportunity to make things, design things of your own choice and test them out – a very fundamental human activity,” says Randy Rettberg of the Massachusetts Institute of Technology (MIT) and Director of iGEM.

Diagram of Cambridge 2009 iGEM project.

Diagram of Cambridge 2009 iGEM project. Dipstick wells contain genetically engineered E. coli. When the sensor detects the substance it sends a signal to the tuner – this ensures that pigment is produced only when the concentration is above a certain threshold (which can be ‘tuned’ to different levels). Each well contains different bacteria tuned to react to different concentrations – higher concentrations activate more wells along the dipstick and warning colours can be used to indicate unsafe levels.

Each team is given a set of parts from MIT’s ‘BioBricks’ Registry of Standard Biological Parts, an open-access archive being developed by synthetic biologists worldwide.

After a crash course in basic biology, the teams use the ten or so weeks over the summer to come up with an idea, design it, model it, build it and test it in the lab, before presenting the final results at a showpiece event at MIT in November.

It’s a daunting task, but one that teams consistently rise to. Successful ideas range from bacteria that detect arsenic in water to a ‘clutch’ mechanism allowing you to control the movement of bacteria.

In 2009, the competition involved 120 universities worldwide. The Imperial College London team placed fourth overall with their idea of creating a bacterial pill for ingestion that would manufacture specific therapeutic proteins and then encapsulate itself to form a ‘micro-pill’. “The overall aim was to design a modular system that could be adapted to produce a variety of drugs,” says Kitney.

But the competition was won by the University of Cambridge team, who provided a simple, elegant engineering solution to an everyday problem. The aim was create a simple visual signal to represent something detected by a biosensor, such as the arsenic detector developed by a University of Edinburgh team in a previous iGEM competition.

They plundered simple, known metabolic pathways from different organisms, using different combinations in E. coli to produce a variety of coloured pigments: orange and red from carotenoids, brown from melanin, violet from violacein and green by knocking out a gene in the violacein pathway. The team created a number of different colour readouts, as well as sensitive tuners that allow the system to respond precisely to input from different sensors.

Imagine you have a dipstick with a range of wells along it, each containing different E. coli tuned to respond to different signal strengths (the concentration of heavy metals in the environment, for instance), and each producing a different coloured pigment in response to that. Testing a water sample will produce a kind of ‘live barchart’ on the dipstick in rainbow colours, with the well containing the most sensitive bacteria at the base of the bar chart, and progressively less sensitive bacteria further up.

“Our hope is to take our parts along with the biosensors that people like the Edinburgh team have produced and put them together for use in the field,” says Micklem.

Student activism

European teams at the 2009 iGEM jamboree event, including University of Cambridge and Imperial College London.

European teams at the 2009 iGEM jamboree event, including University of Cambridge and Imperial College London.

To achieve such feats in just ten weeks is remarkable – and even more so because the participants in iGEM are not experienced scientists or even PhD students, but undergraduates. Yet that lack of experience can also have its benefits in terms of fresh ideas and raw enthusiasm.

“The students at iGEM haven’t been told that things aren’t possible,” says Kitney, “They start doing things that one would have imagined were impossible.”

Professor Paul Freemont, Kitney’s co-Director at the EPSRC Centre, agrees. “The young people who are coming into the field don’t have any baggage. They simply don’t think that engineering biology is impossible, that it will never be predicable or robust enough.”

And iGEM provides almost as much opportunity for the professional scientists as their students. The competition involves just about every academic institution currently involved in synthetic biology in the world, encouraging a sense of community and collaboration, with teams earning extra points for helping other teams, particularly new ones, get set up.

The highlight is the annual jamboree at MIT bringing together everyone involved in one location, infused with the infectious enthusiasm of 10 000 undergraduates.

“The atmosphere is electric,” says Micklem. “The students get to meet everyone in the world who is working this area, right from world-leading labs to those who are just starting out. And most undergraduates don’t work on a big team project or get flown out to a big international meeting. It’s tremendously exciting for everyone.”

Social engineering

The iGEM competition also feeds into itself, and the MIT Registry. Any new parts created in each year’s competition must be sent to the Registry and made available to the following year’s teams. Those that work well are soon picked out because they are reused, retested and revalidated by new teams, filtering what is robust and reliable from what isn’t.

However, not everyone agrees that the BioBricks approach is the most efficient way forward for synthetic biology. As Micklem tells me, large labs with substantial funding can now order their DNA made-to-measure from external companies. This avoids a lot of tedious and slow lab work, and with the price of DNA synthesis falling all the time, this is becoming more cost-effective than working with biobricks.

iGEM: your ticket to adventures in synthetic biology.

iGEM: your ticket to adventures in synthetic biology.

Yet the simplicity of the BioBricks approach allows undergraduates – and indeed non-biologists – to take part, and this is enabling what might be thought of as a form of social engineering. By bringing together large numbers of student life scientists, mathematicians, physicists, engineers and computer scientists, iGEM is seeding a new generation of researchers with enthusiasm for and commitment to the field – a generation who may end up in faculty positions, setting up labs and sitting on grant funding bodies (indeed, Rettberg tells me several iGEM graduates are already on tenure-track faculty positions).

“Biology is at a stage – and not for the first time – where it needs to draw on people and ideas from other disciplines,” says Professor Steve Oliver, Director of the Cambridge Systems Biology Centre. “Things like iGEM can really enthuse young scientists. Catch them young and they can make a huge amount of progress.”

It’s also a great way for universities with no synthetic biology experience to get started. Dr Anne Smith, a computational biologist who this year leads a team from St Andrews University into iGEM for the first time, is excited by the possibilities.

“Synthetic biology is the next step for where engineering is going,” she says. “Biology has a lot of power that it has developed through evolution to do things. Through synthetic biology, we might be able to piggyback on all of that and get it to do things for us.”

And synthetic biology could also make a significant contribution to biology itself.

Says Freemont, “We learn about fundamentals of biological systems by trying to build new systems – how difficult they are to regulate, control, work with, and how biology overcame all these problems. As Richard Feynman once said, ‘What I cannot create, I do not understand’.”

Nevertheless, he says, the application-driven approach is one of synthetic biology’s biggest advantages. “Here is a field with real direction and purpose, not just understanding the fundamentals of things. And when you’ve got that it can be really powerful.”

As a field in its most nascent stages, it’s hard to say what impact synthetic biology will have, or if it really will be the revolution in biology, engineering, science and technology that some think it could be.

“We’re just ten years into synthetic biology,” says Rettberg. “The internet took 30 years to become significant. And the most significant things we only recognise as such after they’ve happened.”

References

The Royal Academy of Engineering. Synthetic Biology: Scope, applications and implications. May 2009.
The Royal Academy of Engineering. Synthetic Biology: Public dialogue on synthetic biology. June 2009.

Image credits: Gos Micklem. jurvetson on Flickr.

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