For most Synthetic Biologists, the idea of engineering life probably conjures up images in your mind of genetic circuits, plasmid maps and fluorescent bacteria. This is where most of SynBio happens: at life’s “software” level, with parts such as open reading frames, promoters and terminators. But there’s also a second side of SynBio that many aren’t familiar with, which engineers life’s “hardware” directly. At this level, the parts become proteins, membranes or even DNA strands themselves. This is what the international BIOMOD competition is all about: building things from the molecules of life.
BIOMOD is similar to iGEM in many ways; both are annual competitions drawing undergraduate teams from around the world. Like iGEM, the BIOMOD competition culminates with a jamboree finale, held in San Francisco. Teams spend the summer working on their project, both inside the lab and out. As part of their work they create a wiki detailing their project, their results and what they accomplish. To make their project more accessible, students also produce a short video that explains what they’ve done to a general audience.
Last year, when I was President of Oxford University’s Synthetic Biology Society (SynBio.Oxford), we decided to organise the UK’s first BIOMOD team. Robert Oppenheimer, then the Treasurer of SynBio.Oxford, had led the winning 2014 UNSW BIOMOD team. Together, we decided we wanted to take a different approach to how most iGEM and BIOMOD teams are organised. Usually a team would be formed by convincing a PI to take them under their wing, hosting, supervising and funding them. Instead, we organized the team such that they had multiple advisors but were not explicitly part of any particular group. We believed this would give the students the best experience possible by giving them lots of independence. That way, they would have the freedom to conceive, design and execute their own project without any constraints from a host lab.
Synthetic Biology is a very interdisciplinary field and competitions like BIOMOD are a great way for students to get a taste of something completely outside their usual area. Rather than focusing on life scientists and engineers, we therefore set about recruiting students from STEM and related disciplines all over Oxford. We advertised in departmental newsletters, through societies, and even pitched to students at the start of their lectures. When the dust settled, we selected a team of four: Hannah Cornwall, a Medical student, Sam Garforth and Martin Veselý, both Biochemistry undergraduates, and Jordan Juritz, a Biophysics student. They called themselves team Riboxswitch.
For their project, Riboxswitch decided to build riboswitches that could regulate translation cooperatively. Riboswitches are small sequences inside mRNAs that form secondary structures controlling translation. They contain aptamers: sequences that specifically bind small molecule targets such as sugars, metals and amino acids. The riboswitch controls translation of its parent mRNA based on whether it has bound its target. In the past, artificial riboswitches had been built. However, they regulated translation in response to their target in a mostly linear way, like a dimmer light switch. To enable applications like biocomputing, riboswitches need to be more like light switches with an ON-OFF dose response; almost no expression until their target reaches a certain concentration, then a very sharp increase to maximum translation. To create riboswitches that could do this, the team decided to build ones that worked cooperatively.
Cooperativity is used throughout nature in a lot of different systems and at different scales. In some cases, it’s used to make decisions, such as when quorum sensing bacteria ‘decide’ to start luminescing when their population reaches the right density. In other cases, it allows systems to alter their properties dramatically over relatively small concentration ranges. Probably the most famous example is the haemoglobin protein that carries oxygen in our blood. Haemoglobin’s oxygen binding is cooperative, which allows it to take up lots of oxygen in our lungs but also release all of it when it reaches our tissues.
To accomplish cooperative behaviour, the team created artificial riboswitches with several binding sites, much as haemoglobin has multiple oxygen-binding subunits. After many computer simulations, scrapped designs and long literature searches, the students identified several different riboswitch designs that they thought could be cooperative. Over the course of the summer, they created many of these and were able to show that several did indeed act cooperatively. Finally, the team demonstrated that their switches could hide or expose the RBS (Ribosomal Binding Site) that controls translation rate, paving the way for their riboswitches to control protein production.
The students won Gold status at the jamboree by completing all the competition’s requirements, finishing in the top 50% of teams and demonstrating that at least one of their devices functioned as designed. Perhaps most impressively of all, their project has now been picked up by collaborators at Bristol University who are continuing to work on cooperative riboswitches.
Taking part in BIOMOD was a great opportunity for the students to delve into an exciting new area outside of their studies, drive their own research and work at the cutting edge of Synthetic Biology. For many of them, it has also kickstarted their interest in SynBio: one is now on the SynBio.Oxford committee, and another is SynBio.Oxford’s liaison officer with SynBio UK, a national-level Synthetic Biology association for students. Whether you’re a PhD student or an undergraduate, organising a BIOMOD team is an incredible opportunity and my hope is that Oxford’s will be the first of many UK teams to come!