• Article
  • Science

Hammer to the anvil: Synthetic biology & the DNA Foundry

How can Synthetic Biology help us to redesign life: from drugs and food through to living factories, or perhaps even teeth-cleaning microbes?

March 11, 2019

Biology has come a long way since Robert Hooke discovered the cell in 1665. Even tools that were considered cutting edge only two or three years ago are becoming obsolete, while nanotechnology and high performance computing accelerate our abilities to decode, understand, and re-imagine the essence of cellular life: using Synthetic Biology.

Synthetic Biology promises to usher us away from beating sparks off the anvil and towards the precise welding together of the building blocks that make up a genome. Not content with merely dicing, splicing and ligating sections of DNA, the field aims to lay bare the bricks that build the walls of life, as simply and efficiently as possible.

From a better understanding of just what it takes to build a genome from scratch, a whole world of creative opportunity opens up. We can, quite literally, redesign life: from drugs and food through to living factories, or perhaps even teeth-cleaning microbes.

Science made simple

In the pursuit of making life more simple - farming wheat to make bread, for example - we haven’t half gone and complicated matters, genetically speaking.

Take bread wheat, for example. Thousands of years of domestication and hybridisation have rendered the genome of this plant barely decipherable - and it’s taken millions of dollars, several continents and thousands of scientists to get just about close to a full genome sequence.

The problems inherent in this complexity are becoming more apparent every day. One such problem is that there is so much information, much of which is repeated, that it becomes difficult to find a signal through the noise, so to speak.

Before, as in ten thousand years ago until just about yesterday, we were - not unknowingly, but relatively blindly - playing with the fruits and fauna of the earth so that they became more manageable, farmable and eatable.

Now we have gotten to that stage, we have recognised the drawbacks of our approach. Dogs die of genetic ailments, wheat plants get ravaged by rust, potatoes become rotten with blight, and our antibiotics can barely cure the most ancient of sexually transmitted diseases.

So, if biology of the past was the analogue version, we are thankfully heading full steam ahead into the digital age of the life sciences (and it’s about time).

We've now arrived at the transection of traditional biological sciences and digital bioscience research

We're now at the transection of traditional biological sciences and digital bioscience research

Problems in abundance

The challenges facing biology are large and potentially daunting.

In the face of global climate change, environmental destruction and the world’s sixth mass extinction event, we must find a way to produce enough food for over 10 billion people come 2060. This is in light of the increased threats to our most farmed crops, too.

Vast swathes of wheat, maize and rice are permanently under threat from pathogens intent on sweeping through, feasting and reproducing on our crop monocultures. We’ve bred most of the resistance out of them.

The Irish potato famine seems like history, but blight is an ever-nagging threat when it comes to global food supply. Diseases are spreading to new areas about as fast as we can breed plants to keep up with them, if not faster.

Modern detection methods are one thing, but viruses, bacteria and fungi have a way of getting around the best defences. It’s not just crop plants that face these emergent threats, but our fauna and flora, too. Notwithstanding the carnage caused to our ecosystems by humans, there are other scourges that threaten species worldwide.

The ash dieback fungus in Europe, combined with the Emerald ash borer in the USA, look determined to wipe out the majority of ash trees in either continent by the turn of the next century, unless something can be done to stop them.

Our global health system, in a similar light, is facing the huge challenge of antibiotic resistance in a world bereft of novel antibacterial drugs. Diseases that had, until recently, been confined to the history books could make a whopping comeback if we cannot find another method to keep pathogenic bacteria at bay.

Open quote marks

Be it overprescription, overuse, or the widespread misuse of antibiotics in healthcare and agriculture, the fact is that not a single new generation of antibacterial drugs has been discovered in decades.

Closing quote marks

Then there’s our global waste problem. The oceans are becoming a teeming plastic wasteland, which clogs the stomachs of sealife and seabirds alike, adorns our beaches with tints of red, blue and yellow, and sits in banks stretching for miles atop the surface, yet there is little we have in the way of breaking all this down.

It’s about time that biology had a shakeup, and here it is.

Open quote marks

The oceans are becoming a teeming plastic wasteland, which clogs the stomachs of sealife and seabirds alike, adorns our beaches with tints of red, blue and yellow, and sits in banks stretching for miles atop the surface.

Closing quote marks

Genetic Engineering 2.0

For a time, now, there has been a war raging, metaphorically speaking, over the GMO. The genetically modified organism, the bitter kernel in the sweetcorn.

Whatever the arguments for and against (the for far outweigh the against), there have been great successes. We can insert the DNA of one species into another, with desirable effects that can reduce losses from pests and disease, while maintaining strong yields in times of environmental uncertainty.

There has been further advancement in this field with the arrival of CRISPR-CAS9 and related technologies, which have hailed the advent of “genome editing,” taking more of the randomness out of genetic engineering.

Now, however, we have reached a much more desirable phase in engineering biology. Why mix and match, when you can start from scratch?

This is where places such as the DNA Foundry at Earlham Institute, and Synthetic Biology, come in. Not content with simply editing genomes, the DNA foundry, along with four others in the United Kingdom, aims to establish a pipeline for the rapid construction of novel DNA, made up of its very building blocks.

The Earlham DNA Foundry uses the latest technologies for sample biostorage and rapid DNA assembly

The Earlham DNA Foundry uses the latest technologies for sample biostorage and rapid DNA assembly

Microfactories

After all, organisms and cells are essentially living factories packed with nature’s incredibly efficient (mostly, RUBISCO notwithstanding) micromachines. The deeper down you look into a tissue, and then a cell, the more clearly this becomes apparent.

Zoom into the bottom of the leaf, and the doors of the factory are revealed - the stomata through which gases diffuse into and out of a plant. As long as the doors (guard cells) are open, CO2 is free to diffuse into the palisade and mesophyll layers of the leaf, the sugar factories of plants.

Zoom into the palisade factory, and it is compartmentalised further into departments, the organelles, allowing an efficient distribution of activities to occur. The most important of these, the chloroplasts, equipped with one of nature’s most important production lines - the thylakoid membrane.

Zoom into the thylakoid of the chloroplasts, and we see the machinery at work. On the anvil, the Manganese-dependent water-splitting centre, sunlight energy enables the plant to split a water molecule, releasing some very excited electrons.

Through an intricate passage across photosystems I and II, via some even more excitable chlorophyll, plastoquinones, cytochromes and ferredoxin, the electrons are passed up and down the production line until, eventually, some NADP+ is reduced to NADPH and joins some ATP to facilitate the assimilation of CO2 into glucose (and back out again via the most inefficient enzyme in the world of biology, rubisco).

Zoom further into the chloroplast, and we stumble across the chloroplast’s unique, circular, formerly bacterial genome, which contains the instructions to build many components of this incredible entropic energy dispersing mechanism.

Within this blueprint, arranged in a small, circular (or probably branched linear) piece of DNA containing around 100 genes, are individual instructions for Rubisco - the world’s worst enzyme - along with each photosystem, cytochromes, ATP synthase and other enzymes.

From a complex plant factory, we get to the basic instructions: a tiny ring of information only 150 000 letters long.

Open quote marks

On the anvil, the Manganese-dependent water-splitting centre, sunlight energy enables the plant to split a water molecule, releasing some very excited electrons.

Closing quote marks

Synthetic biology

Synthetic biology aims to work out the component parts of this cellular machinery, and how to build it back up from blocks of DNA sequence.

Once we understand what each individual block of information contributes to the construction of these cell factories, we can rearrange them from scratch to perform different, or even novel, tasks.

Just imagine the possibilities. From the carbohydrates generated in photosynthesis, between them plants make over 50 000 different types of secondary metabolites, which make up drugs, flavours, smells, vitamins and more.

Once we understand how plants make these, at the most intricate level, we can rebuild these machines to make microfactories of our very own. Multiply these millions of times over into a full plant, and millions of times again into a field, and a million fields more - we have the capacity to grow the answers to many of the starkest challenges that we face in the future.

From drug discovery through to generating novel industrial compounds, with synthetic biology we might scrap the polluting manufacture from factories and mines in favour of a more sustainable, living option. Maybe we could even make rubisco more efficient.

We are now at a stage where we can sequence the genome of almost any organism on earth in a matter of days. Even a couple of years ago, this still required international consortia and millions of dollars.

A recent release of the most up to date wheat genome showed that now, with advances in scientific computing and next generation genome sequencing, this can be done with a relatively small group of researchers using the right tools.

The ability to understand the very components of life is becoming exponentially greater with every passing second, as is the ability to build them back up again.

Open quote marks

Just imagine the possibilities. From the carbohydrates generated in photosynthesis, between them plants make over 50,000 different types of secondary metabolites, which make up drugs, flavours, smells, vitamins and more.

Closing quote marks

DNA foundry

High throughput DNA sequencing requires pipelines, and synthetic biology is no different. Robots can process vast cDNA libraries that help us to decode a wheat genome in days, and what helps break a genome down can help us to build it back up again.

Using standardised biological components, places such as the DNA foundry at Earlham Institute provide the potential to revolutionise the speed of research and development while minimising inputs through miniaturisation of the entire process down to the nano level.

An automated pipeline can not only assemble and sequence bespoke sections of DNA, but can be integrated with multi-omics and phenotyping platforms to find problems to today’s important biological questions.

Alongside initiatives such as OpenPlant, which facilitate the sustainable and ethical reprogramming of biological systems for improved bioproduction, we are not far away from realising many of the answers to these questions.

We could even, one day, fulfil the dream of John Cumbers, CEO of SynBioBeta, whose dream synthetic organisms are “probiotic bacteria that you drink once, which are engineered to remove all of the food waste and plaque that gathers in and around your teeth and gums.

"They’ll line your mouth and throat, come out at night to do their business and clean everything, then in the daytime they’ll disappear again back into your mouth and throat before you wake up. We’ll remove tooth decay, you won’t have to go to the dentist any longer. You won’t need to floss, you won’t get fillings, you won’t need to replace teeth, you won’t have to have teeth removed - imagine that."

Of course, there will be challenges associated with trying to build more complex pieces of synthetic machinery; we still don’t fully understand every aspect of what makes up a plant or an animal genome.

However, as anyone who has tinkered with engines will know, the best way to understand how something works is to take it apart, then try and figure out how the pieces go back together again.

By going back to the very nuts and bolts, synthetic biology might just help us to better assemble the bigger picture.

The Earlham DNA Foundry uses many of the latest proven technologies including automated liquid handling systems to scale-up DNA assembly.

The Earlham DNA Foundry uses laboratory automation for nano-scale modular DNA assembly
Open quote marks

An automated pipeline can not only assemble and sequence bespoke sections of DNA, but can be integrated with multi-omics and phenotyping platforms to find problems to today’s important biological questions.

Closing quote marks

Article author

Peter Bickerton

Scientific Communications & Outreach Manager