In the twilight depths off the west coast of North America lives a small and graceful jellyfish floating apparently aimlessly through the void. Who would have known that this humble jelly—Aequorea victoria—was set to revolutionise cellular biology in the latter half of the twentieth century. Along the rim of the jellyfish’s bell (the propulsive body) lies a ring of light-emitting organs which, in the blackness, produce an electric green glow that wouldn’t be out place in a Ghostbusters film. This luminescence can be attributed to a chemical mechanism based around the molecule known as the Green Fluorescent Protein (GFP), synthesised by the jellyfish. Earning those involved in its discovery the Nobel Prize in 2008, GFP has been the key to unlocking the potential of biological imaging over the last 25 years.

The light organ houses two molecules essential for the light reaction: aequorin and GFP, working in conjunction. By catalyzing the degradation of the protein luciferin, aequorin causes blue light to be released. Rather than emitting this blue light, the photons are instead used an as energy source to activate the fluorescence of GFP. GFP has an excitation peak at the wavelengths of 395 nm and 475 nm—corresponding to blue and UV light. This means that it will most efficiency absorb light in this range of the spectrum. Absorbing this light leaves GFP in an unstable state with ‘too much’ energy, being described as excited. Emission of green light at the wavelength of 508 nm, energetically lower than that it absorbed, returns it to its stable state.

Green light is rare in the ocean depths, meaning that an organism that can luminesce in such a way will be more obvious in its surroundings, allowing it to attract prey and confuse predators. But how is this relevant to cell biology in the laboratory? In 1992, American scientist Douglas Prasher sequenced and cloned the wild-type GFP gene. Over the following few years GFP became the darling of molecular genetics, a result of our ability to fuse the gene onto the beginning or the end of any other gene in any organism.

If inserted into an embryo, every cell in the body can inherit the GFP tagged protein. When the resulting organism is exposed to UV light it then glows green. This allows scientists to track both the distribution and the concentration of the protein throughout individual cells or through the organism as a whole, depending on which protein is tagged with GFP. We can see the trafficking of the proteins through the cell in real time, highlighting a host of cellular processes from protein packaging to the structure of the nuclear membrane.

Over the course of its history GFP has been constantly engineered and modified, transforming it into an increasingly more effective and versatile tool. A whole spectrum of different colours of fluorescent proteins have now been engineered. By using a red-producing variant of GFP, scientists have found success in diagnosing cancer since, due to its longer wavelength, red light can travel further through intervening tissue.

On a grander scale, one couldn’t discuss GFP without bringing up the glow-in the dark rats, cats, rabbits, pigs, monkeys…you name it. Due to its obvious but relatively benign nature, GFP serves as one of the earliest genes used when trialling an organism with genetic modification, as a proof of the technology before more complex manipulation is attempted, with wide implications especially within medicine. We will soon reach the point where we can easily extract vaccines from cow’s milk, and produce disease resistant pigs.

The story of a simple jellyfish that has gone onto transform the very nature of molecular biology and medicine is a testament to the resourcefulness of science and humanity as a whole. It proves that the most useful of tools can have the most unlikely of origins, and should serve as a needed reality check. With every extinction, we say goodbye to another jewel in the biological crown, the vast wealth of unique genetic information that the organism possessed vanishing often forever. Who knows how many ‘GFP’s’ we’ve already lost.

“Take a look at the items on your desk: a lamp, various iDevices and a house plant. Which of these is the most advanced piece of engineering?” asks Dr Jason Kelly, CEO of the synthetic biology company Ginkgo Bioworks. He argues the case for the house plant: a self-sustaining, self-replicating and selfrenewing system. “Imagine what a self renewing iPhone would do to Apple’s profit margins!”

Biology has evolved machines of incomparable sophisitication to manmade devices, however synthetic biology, the fusion of engineering and biology affectionally known as ‘synbio’, is providing tools for scientists to exploit the genetic machinery that organisms use to live and co-opt it for novel purposes. From bacterial perfume to computing DNA, the applications are seemingly limitless, as the Oxford 2017 iGEM (International Genetically Engineered Machine Competition) team discovered when they attended a conference at the Royal Society in London.

The first speaker, Professor Christina Smolke from Stanford University, explained how her group engineered a yeast opioid production line, allowing more efficient production of the poppy-derived pain relief molecule than traditional extraction methods from its natural source. Transplanting the poppy pathway into yeast required knowledge of the protein machinery (enzymes) and genes that encode them in every stage of the natural pathway. From here, the researchers turned to other organisms to mine for alternatives. For efficiency, different stages of the pathway were segregated to different sub-compartments of the cell, much like the specialised buildings of a production factory.

Then came Dr Jason Kelly, whose Boston based company Ginkgo Bioworks is taking advantage of the falling cost of genetic engineering to expand it to new markets in the fragrance, flavour, and food industries. Their latest venture is a microbe produced version of an extinct flower’s scent. Consult Dr Kelly and his team with a product idea and they will endeavour to find a way to make a bacterial device to meet your needs. The innovation takes place in an impressive 40,000 square-foot facility, more akin to a sci-fi film set than a science lab, endowed with the latest robotics and automation. Automation is crucial to synthetic biology’s design led approach to replace time-consuming trial and error experiments. Dr Kelly’s presentation stood out in capturing the ‘blue sky’ thinking of the field, and we were excited to discover that he was part of one of the first iGEM teams.

This same approach has applications in more conventional industries while still retaining this ‘outside the box’ thinking. Dr Jeremy Shears from Shell discussed the potential of a synbio solution to the energy problem, envisioning fuel producing microbes and novel energy carriers made by photosynthesis. Many of these applications are a long way off, yet the urgency of the growing energy crisis makes advances in this field vital.

The importance of drugs derived from natural products highlighted in Professor Smolke’s presentation was revisited by Pfizer researcher Dr Edmund Graziani, who described these chemicals as “privileged” because they have been fine-tuned by evolution. However, he explained that in the past only a subset of these chemicals were suitable to be developed into drugs because they had to be small enough to enable them to be properly processed by the body. Not only did this limit the compounds that could be developed, but also left many diseases “undruggable”. Dr Graziani argues the case for creating a microbial machine that can perform “directed evolution”: the bacteria would take existing natural products, modify them, and spew out only the most promising potential drugs. To realise this approach, however many technical hurdles must be overcome.

A recent addition to the synbio toolkit, the development of techniques to incorporate unnatural amino acid building blocks into proteins in vivo is proving useful in pharmaceuticals and beyond. Usually cells are limited to using only 20 of these building blocks, so expanding this repertoire by adding phantom amino acids could greatly enhance diversity. What’s more, the scientists can choose the precise site into which to introduce the unnatural amino acids to specifically decorate the protein with chemical labels. These are useful, for example, in making the protein visible under a microscope or in allowing it to be attached to a drug delivery vehicle.

The final speaker, Microsoft’s Dr Andrew Phillips, presented research into “bio-computing”, explaining how knowledge of how cells compute is being exploited to programme DNA and organisms. For example, the “consensus algorithm”, which causes participants to agree to do the same thing, was ‘invented’ and utilised by cells as a means of controlling cell division. There are exciting advances here, but it seems that at the moment the biology is more complicated than the computer science: biology is more unpredictable and noisy than electronics so we must be careful not to overstretch the analogy of “genes as circuits”.

I took a lot away from the diversity of the talks, not only inspiration for iGEM but also a better understanding of the current achievements, future promises, and limitations of the field of synthetic biology. The scope of synbio applications we learnt from the conference certainly hasn’t helped us narrow down ideas for our own project, but we left excited by the fact that we may be able to contribute to this rapidly-expanding area of biology.