The Microbial Machine – What does Microbiology mean for SynBio?

Synthetic biology (or ‘synbio’ as it is often abbreviated) is one of those fields in biology which is hard to define. Most tend to agree that it involves in some way the engineering of biological systems, but the field evolves and changes so rapidly that it’s hard to pin a universal definition to it before something ground-breaking turns our conceptions upside down. Synbio aims to modify organisms so that they will be useful or beneficial to humans or the environment, with many modified organisms already produced, such as fish that fluoresce in contaminated water (and their commercially available counterparts that always fluoresce – a favourite in home aquariums in the USA), bacteria and yeasts that produce pharmaceuticals, and modified crops with greater harvests or hardiness.

algae tanks.jpg

One avenue of synbio looks at harnessing algae metabolism on a large scale

With such a diverse field fuelled by many areas of biology, engineering, chemistry, physics, and even more, it’s easy to get lost in what this can all mean – even researching for this article I went down so many rabbit holes I almost forgot what I was going to write about! Synbio is extensive and multidisciplinary, so as a microbiologist who’s just moved into synbio myself, I’ll try and take a look at where we stand in this field that is simultaneously new on the scene and a cornerstone of modern science.

The first piece of microbiology that comes to mind when someone mentions synbio is usually the ground-breaking, proof-of-concept stuff: the latest articles that hit the newspapers and get blogged about all the time online. A few years ago we had the first ‘totally synthetic’ bacterium – a Mycoplasma strain whose entire genome had been designed artificially, with not a single base pair in the cell that wasn’t intended to be there by the scientists. A little more recently, from the same lab, we had the ‘minimal genome’ – the already tiny genome of Mycoplasma mycoides had been stripped down as much as possible. The result was the smallest genome they could possibly obtain for the organism to survive, with just 473 genes. Even more recently, my twitter feed for the past few days has been dominated by news stories of great strides made in creating an artificial leaf – which uses photosynthesis to convert carbon dioxide and water into biofuels – a hot topic in synbio. Of course in a field so rapidly evolving and changing, ‘news’ quickly becomes ‘old news’ as the next big thing is published and we yet again reconsider what we thought possible – in a strange way I can’t wait for the next big story to come out and make this blog post seem completely outdated.

Minimal Genome Mycoplasma.jpg

Dubbed ‘Syn3.0’, the minimal genome bacterium has less than 500 genes

Next up in microbiology’s synbio viewfinder tends to be what I think of as the bread and butter of the field: metabolic and/or protein engineering. I’m cheating a bit here because this area is so vast and important that it would be impossible to do it justice. The general (but not exclusive) aim of these fields is to create a microbe or protein that generates a useful chemical that otherwise would be costly to obtain due to its rarity or difficulty in chemical synthesis. One of the most well-known examples of this (or at least one of the most widely taught examples) is the synthesis of artemesinic acid – a precursor to the antimalarial drug artemisinin – in the yeast Saccharomyces cerevisiae. This involved adding new genes to the yeast, and altering the expression of the yeasts own genes and modifying the properties of individual proteins to optimise the amount of artemesinic acid produced. In the same vein, scientists have also created a plethora of different microbes that produce biodiesels, bioplastics, alcohols, and pharmaceuticals – it would be ridiculous for me to go into detail on all of these and the many more case studies out there.

There is also a lot of interest in microbes engineered to do the opposite: the breaking down of harmful chemicals in the environment. There are collections of organisms that are able to break down crude oil from oil spills, and treat run-off from decommissioned mines in order to prevent the release of toxic chemicals to the environment. This area is also huge – in fact I already wrote a blog on it here.

mine runoff.jpg

We can treat acid mine run-off with bacteria made more effective by metabolic engineering

For most people, the trail of thought on synthetic microbiology ends somewhere on the slopes of the mountain of metabolic and protein engineering – and can you blame them? The topic is not only vast, but also highly profitable and full of interest from scientists, industrialists, policy experts, and the general public. However, for those that climb to the top of that mountain and look past it, there is an extraordinary wealth of synbio topics for microbiologists to get stuck into. These often weird and wonderful areas of research tend to occur when biology collides with other areas of science in fantastic ways.

One of these collisions is that of biology and computer science. The idea of a living computer sounds like something out of science fiction, but as time goes by we get closer and closer to a reality where we are able to use bacteria for our computational needs.

The development of the field of systems biology, which takes a wide-angle view of cellular processes to look at the underlying systems, has led to many similarities being observed between living cells and computer programs. This led to an avenue of synthetic biology that uses the way genes are transcribed to simulate computational processes. The difference here is that instead of a 0 and 1, you have activation and repression of genes. What started simply in the ‘toggle switch’ – a simple ‘on/off’ system for gene activation – has blossomed into a field where it is now possible to do everything a simple computer can do but using bacteria. In theory, at least.

The crux of computer programming is logic gates – you might not be familiar with this but you use them every day. They’re statements like ‘if the light switch is on, the light will be on’. These are expanded with logical operators – ‘and’ and ‘or’ are examples. ‘If I inoculate my culture and put it in the incubator, my cells will grow overnight’ – you have to have both things either side of the ‘and’ for the outcome to happen. There are 16 possible logic gates in computer programming, and all of these have been replicated in bacterial DNA. We even have bacteria that can count – they use a recombinase to alter sections of their own DNA to express different proteins depending on which count they’re on. With all of this, simple genetic computers can be constructed in a cell. The scope here as that there is an additional layer of information in this system that can be exploited. We don’t have 0’s and 1’s, we have concentrations of unique proteins – what this means is that as the field develops, we should be able to exploit this to create complex systems that an ordinary computer cannot replicate, or at least not without a lot of work.

Biological computer kills cancer cells

This ‘biological computer’ uses logic gates to kill cancer cells

One of my favourite things to think about when it comes to synbio is at the forefront of a field seldom associated with the classical sciences we were taught at school: architecture. I’ll admit it’s not immediately obvious how something as small as a microorganism can be useful for an architect (at least not one that doesn’t work on the micrometre scale) but an idea that is becoming more and more popular is one that has come to be known as ‘The Green Tower’. The premise is simple: you take a skyscraper (or build one, whichever works for you), and you incorporate, using tanks or pipes of some description, algae.

Green Tower Chicago Loop.jpg

A design for the towers in Chicago’s Marina City – going from grey to green

Okay, obviously there’s a little more to it than that. The idea is to use algae (often in conjunction with other technologies such as carbon dioxide scrubbers, wind turbines, phyto-purification, and other eco-tech) to remove CO2 from the atmosphere. So far what I’ve described about green towers isn’t really considered synthetic biology – at least no more than planting a tree to take up carbon dioxide would be considered synthetic biology – that part comes in with what you get the algae to do next. The answer isn’t really fixed, and tends to lean back on the previous point of metabolic engineering. One option often considered is using the algae to produce biofuels, which can be extracted and then used to power the building itself. Another common option is to use algae that generate a lot of biomass, which is the siphoned off to use as a nutrient source for vertical farming – another eco-tech feature common to the green tower theme. Others design these algae to absorb harmful smog chemicals and neutralise them, reducing air pollution in major cities.

A quick search for ‘green tower’ comes up with many fantastic architectural designs for ecologically conscious skyscrapers. Amongst these you’ll find a mix of architects’ quick ideas, more involved proposals for new or remodelled buildings, and even designs for entire green cities. One of these green cities is already under construction in South Korea – the city of Gwanggyo near Seoul designed by Dutch firm MVRDV. Another, perhaps more ambitious design comes from Vincent Callebaut Architectures, who has put forward his radical ideas for how Paris should look in 2050. Both designs include vast usages of green technologies, with algae featuring heavily in a variety of different contexts. Whilst many designs seem incredibly fantastical – floating cities or submarines that rid the water they float on or through of pollutants, skyscrapers the size of mountains that are entirely self-sufficient, and many more – there’s plenty of research being done into the feasibility of all this. The main problem here though is that scaling up from the lab to a skyscraper isn’t so easy, so whilst we might be hearing about green towers for a while to come, it could be a little while before the cities are green rather than grey.

Paris 2050 Vincent Callibaut.jpg

By 2050, could Paris be the green capital of the world?

And with that slight touch of pessimism comes the real issue with a lot of synbio projects. On paper, a bacterial computer or a photosynthesising skyscraper might seem amazing, in practise it is seldom so simple. Most of the bacterial ‘programming’ we have so far has to be fine-tuned extensively just to carry out a simple function, and although the use of CRISPR-Cas has improved gene editing to optimise things, it stands that bacteria capable of any complex computing might be a bit of a far flung ideal. The same with my favourites, the green towers – there are hundreds of designs out there but very few come to fruition. There are just too many unknowns when it comes to living organisms for us to reliably use them for these complex applications.

However, with a field evolving so rapidly, great strides will again be made soon. Just as it can be impossible to predict how a microbe will react when you change its genome, it’s almost impossible to predict where the next great discovery in synthetic biology will be, and how it will both push humanity forward and develop our understanding of the world we live in.

 

Robert G Millar (University of Warwick)

Society for Applied Microbiology



Categories: Feature Articles

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