The takeout on Synthetic Biology- what can takeaway teach us about biological engineering?

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Takeout can teach Synthetic Biologists a thing or two about engineering and building applications more effectively.

by Serena Marletta and Alan Walker

Another long workday is coming to an end… today it didn’t go well at all. That DNA fragment you were striving to clone has failed again. What’s going wrong?

Maybe traditional restriction/ligation is not working. You could try Gibson assembly, it worked for your lab mate last week. Or maybe it’s the vector? You check and discover it was designed by the previous post-doc and a manual sketch is all you have.

The vial cap only says “pBS” and now you are not sure if you are working with the right vector. Project review is close, and you want to optimise your next steps.

But it’s 7:36 PM and your stomach is growling. You only had time for a sandwich at lunch. No use battling on. These problems can wait. It’s home time. It’s dinner time.

When you get you home, you race to the kitchen to conquer the fridge… E-M-P-T-Y!!! You had such a busy week that you forgot to do to the groceries. Again.

Once this would have meant disaster, but this is 2021… You smile as your hand reaches for your phone. Oh yes, your belly will be full tonight. You open that takeout app, find what you fancy and hit order. Before long, you’re sitting in front of a Bento box from your favourite sushi restaurant.

hand drawn sketch of a vector

A manual sketch of a vector. One of the cardinal sins of Synthetic Biology best practice.

What was a disaster of a day has been saved- thanks to a little indulgence in your favourite takeout. And it was all so easy. So easy and so seamless that you don’t even stop to ask yourself; how did they do it?

It’s just a takeaway after all. Nothing new right? What’s so difficult about that?

Well its a lot more difficult than you might think.

And so maybe, there’s something as Synthetic Biologists we could learn from your takeout app. If they can deliver value so effectively that you don’t even notice it, they must be doing something right.

Takeout and Synbio stacks

Let us start with an observation about stacks, because much like your takeout app, synbio apps are dependent on a tech stack.

Typically represented in layers. Stacks allow value to be delivered more effectively through specialization in narrow areas of expertise along a supply chain.

SynBio is still developing its technology stack. It is afterall a young discipline, and is evolving all the time. In comparison, the  enabling technology of your takeaway app – the takeout food itself – is as old as antiquity. The digital app is just the latest in a long line of innovations.

A simplified view of the evolving synbio stack is as follows:

A simplified representation of the SynBio stack.

At the top of the stack are the applications and design layers. This is where most researchers we speak to prefer to work. These layers map to the design and test layers of the DBT cycle and it’s where creativity and innovation are most important.

The layers below “Reagents” and “Process Execution” are operational by nature. At these layers you find the enabling technologies of synthesis, assembly and automation.

But for stacks to function effectively requires adherence to the principles of engineering by everyone involved. Those same principles of standardization, decoupling, modularity and characterization that we struggle with in synthetic biology.

Well clearly they have already been mastered by your food delivery app. So let’s look a little deeper to learn how they did it.

Decoupling the stack

Your takeout is possible because of effective decoupling of expertise. Chefs, programmers and hardware engineers specialize and cooperate within their own tech stack. In doing so they can connect you to every restaurant in a 10km radius. 

Through decoupling, each element of the stack delivers value more effectively then if one tried to do everything.

Which brings us to a significant challenge in Synthetic Biology; our tech stack is not yet fully decoupled. Currently work to deliver results in the applications layers requires expertise in lower operational layers.

DNA fragments still need to be assembled, cloned, transformed and verified in-house before researchers arrive at a testable prototype. Which means labs whose focus is on the application layer, must also coordinate expertise in the process and reagent layers.

Nor is design decoupled from the constraints of manufacture. Biological designers must consider technical issues of manufacture such as codon optimization, repeats and other forms of complexity from the offset.

Currently work to deliver results in the applications layers requires expertise in lower operational layers of the SynBio tech stack.

Synbio chefs – the biofoundries

To the rescue are the chefs of the synbio stack: the biofoundries. Their role: to decouple the lower operational layers of the tech stack with the higher application and design layers.

By doing so, the result is to integrate and streamline the “Build” and “Test” phases of the DBT cycle. This is what we do at Doulix, but we are not alone.

The Global Biofoundry Alliance brings together university mega-labs and private initiatives to support a growing need for integrated DNA manufacture and testing. And as the name suggests the DAMP lab (design, automation, manufacture and prototyping) is about integrating as much of the stack as possible.

Even the big guy Ginkgo has invested in its own synthesis capacity to offer more integrated, end-to-end services.

The stack is vertically integrating. Which is good news for biological designers and engineers like yourself. Increasingly you’ll have the choice to perform less of the repetitive, operational work. Which in turn allows you to pursue greater scale and creativity at the application layers of the stack.is

Biofoundries are vertically integrating lower levels of the stack to free applications specialists to pursue research more effectively.

The Menu – modular part libraries

There is a certain modularity to cooking. Take a pro cooking course and you’ll learn techniques not recipes.  Expert chefs can swap ingredients and techniques to pursue infinite creativity in the kitchen.

Much like the chef, the biological engineer requires modular parts to make the infinite potential of his designs more tractable. This after all, is one of the key principles of Synthetic Biology.

Currently we are still very much in the process of exploring and formalising modular parts for engineering. And with the full armoury of biology to explore, it is a task with no clear end date.

A search on “Publish of Perish” for keywords associated to “toolbox” “parts” and “synthetic biology” via the Google Scholar database, shows a steadily increasing trend in publications since 2000.

Search results on the google scholar database via publish or perish. Keywords searched: Biological Parts, Tools, Toolbox, Modular. Search constrained to publications with “Synthetic Biology” in title.

This is a positive sign for the field as the discussion on biological parts is clearly increasing. However, many of these articles describe new tools, parts, chassis and techniques, further adding to the toolbox of Synthetic Biology

Trouble is, these high rates of change can make the task of standardization much more difficult. Standardisation requires limiting the size of our toobox for tractability. This is the goal of organisations like Bioroboost and SEVA, who aim to limit the SynBio toolbox to a selection of well characterised chassis, backbones and parts.

Part usage and behaviour

On the other side of the modular parts equation are use habits. And the signs are less positive for Synthetic Biology puritans. That’s because part usage is proving slow to be adopted by researchers.

Only a small portion of the synthesis requests we receive at Doulix are for publicly available parts. Of those we do receive, backbones and reporter genes are the most common.

We see that biological engineers still opting for custom designs. They still prefer designing from scratch appropriate sequences for their specific platform, rather than risk research on reutilising unknown parts.

Organisations like AddGene make it easier than ever to share parts and vectors but as part registries become prevalent their widespread usage is lagging.

A quick check on google trends for the global usage of the term “biological parts” shows a highly variable but positive trends over the last five years. Thats a good sign but the total interest in biological parts is still small.

Google search trends for the term “Biological Parts” over the last five years. n.b, Y axis shows relative search volumes between 0 and 100 and does not represent actual search volume.

Compare that to searches for DNA synthesis in the last five years and we get a sense of the relative importance of the practice.

Google search trends for the terms “DNA synthesis” (red) and “Biological Parts” (blue) over the last five years.

Modularity is increasingly adopted

The good news for Synthetic Biology puritans is that all is not lost. If public parts are not necessarily widely used, we do see the concept of modularity growing in practice.

Within Doulix’s synthesis services, we see increasing use and reuse of modular parts created privately by labs for their specific platforms. This is particularly true for CDS components and custom backbones.

This trend is reflected in pages views from our collections. Six of the top ten pages viewed in 2020 were private parts created by labs and saved within our collections.

So, while the menu of Synbio is increasing, old habits die hard, and biological engineering still remains highly custom.

But the good news for supporters is habits are changing, and parts are being used more frequently within research groups.

Position
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The top ten page views of the Doulix collections show that six of the ten most popular constructs were privately created.

The Party – Collaboration in SynBio

It’s the company that makes a dinner party. You’re covering the food; cheating with another takeout.

Friends bring the drinks and dessert. And, you’ve got that friend who loves to play DJ via his phone. Together you have the recipe for a memorable night. Teamwork makes the dream work as they say.

In synthetic biology, teamwork is not only important but critical. At the intersection of a number of disciplines, projects require input from an array of experts.

In our story, you were faced with a common problem. Cloning issues. A manual sketch of a vector. Fragmented databases. No single system of project management. No clear way of understanding what worked and what didn’t.

A lack of standards lead to failures of effective collaboration. Because behind the push for standaridisation is the need for better collaboration.

Yeast 2.0, the program to build a synthetic yeast genome, has engaged with over 20 groups and hundreds of students. They are currently approaching the end of their objective to construct the 16 chromosomes of baker’s yeast.

The project is brought together by a range of standardized tools and processes, partly developed in house, to coordinate the work. From software to assembly practices to design processes.

The project tackled standadisation to allow for more effective collaboration. And through coordinated teamwork are creating a synthetic yeast genome for a fraction of the cost it once took to synthesise it.

You see, organisations that promote standardization, such as Bioroboost and SEVA are promoting at their core, collaboration.

They underline how a need for collaboration is driving standardization from the grassroots of Synthetic Biology. And how by doing so, we are able to achieve more than we could do alone.

Organisations that promote standardization, such as Bioroboost and SEVA are promoting at their core, collaboration.

So what are the key takeaways? 

Keep on collaborating. Collaboration drives standardisation which underpins the evolution of the Synthetic Biology stack.

Pick from your menu of modular parts. Whether it is a private or public collection; supporting modularity helps build the well characterised toolkit we need for the future.

Know your specialty and consider decoupling your work. Solutions are arising to allow for more effective R&D at the applications layer, specialise at what you are good at and leave the rest to your stack partners.

With all this talk about food…

Still here? You must either love your takeout or you love your DNA. Which means you’ll love this…

We’re giving away €30 in vouchers for your favourite takeout app! After all nothing brings people together like food. And we all need a little togetherness at the moment.

Claim your voucher before the 15th March to receive your special offer code.

Use the code next time you order DNA and reagents from Doulix and you’ll be tucking into your favourite takeout in no time.