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As part of our new book “What’s Your Bio Strategy?” we’ve interviewed dozens of entrepreneurs, business leaders and academics working on synthetic biology. The following is an excerpt from one of those interviews. To find out when the book goes on sale subscribe to our newsletter here.
The bioeconomy is much bigger than recombinant insulin or genetically modified corn. Increasingly, ordinary industries outside medicine or agriculture will be transformed through the adoption of biological technologies… Intense small scale innovation, coupled with biotechnology, has allowed microbrewers to gain a share of the beer market and be more profitable than traditional macrobrewers. The transition to a bioeconomy is just beginning and the years of disruptive change are still ahead.
- Rob Carlson, Microbrewing the Bioeconomy (2011)
Digital and robotics are transforming manufacturing. In fact, according to Lisa Caldwell, EY Americas Advisory Industrial Products Lead, Lisa Caldwell, “the advanced manufacturing technology revolution has only just begun.”
Digital and robotics are only part of the manufacturing revolution and synthetic biology’s impact on manufacturing has barely just begun.
To understand how, we reached out to Rob Carlson, the author of Biology is Technology. Rob is one of the world’s leading experts on synthetic biology and in 2001 has published an essay in The Economist titled, The World in 2050, where he first mentioned “distributed biological manufacturing.”
Until recently, biotechnology had no tool stack.
Our world is the result of a tool stack that reaches from computer-aided design (CAD) on a laptop screen to machines that manufacture products. A suite of computer applications and application program interfaces (APIs) makes it easy to take a design from a laptop, move atoms around with a printer, make stuff, and ship it out the door.
The Economist just published an article on a motorcycle company that went from whiteboard to a complex, manufactured product in less than three years. That’s quite fast for a motor vehicle. Computer-aided design, engineering and simulation systems made it possible to create and test the motorcycle long before anything physical was built.
The commercial actually opens with a footnote saying Megablocks, a Lego competitor, were used in the commercial. In a separate conversation, Carlson confirmed there must have been trademark issues between Lego and Honda but “obviously they are Legos. The point is that all the viewers identify with Legos and what they can do.”
When I was writing Biology is Technology, I started using the Honda Element commercial as an example of integrated design for manufacturing. It shows thousands of Lego building blocks coming together to form the Honda.
The narrator says, “Every piece has a purpose.”
What he doesn’t say is that Honda can – you can – simulate them all before you build.
The design-build-test cycle is so well understood for most products of mechanical and electrical engineering that in many instances you can go straight from simulation to manufacturing. Boeing did this to design and build the 777 – the first commercial airline designed and tested entirely on a computer. Boeing built the first airframe and a test pilot flew it straight away.
But biology is different.
You can’t transfer what works for designing and manufacturing motorcycles or airplanes to biology. Yet. However, the technologies we need to get into place are maturing very rapidly.
Three things in particular have changed recently.
First is the development and deployment of quality systems in biological manufacturing. These are common in many other kinds of industries, but outside of pharmaceutical manufacturing they have been rare in biotech.
Second is the recent arrival of design for manufacturing in biology. We aren’t at the point where you can design a new organism on a laptop, simulate it, send the manufacturing instructions to automated prototyping instrumentation, then ship that recipe off to manufacturing. But those pieces are coming together much faster than I expected just a few years ago.
Third, it is now possible to design enzymes with new functions and to design new enzymatic pathways that can be used to make entirely new products.
When you put these three developments together, then you start to recapitulate in biology the engineering infrastructure that underlies the rest of our economy. Again, we have a lot of work to do to realize the final capability, but the pieces work, and they are coming together.
Here are a few examples:
The fundamental ability to apply design and automation to gene and genome design has been missing until now. To engineer a cell and scale its growth to produce a product required designing dozens of experiments with hundreds of parameters at the same time. It had to be done precisely in a way that is reproducible. But it was all done manually. That hampered reproducibility. There was no way to operate the different instruments required to run an experiment.
Amyris, one of the first synthetic biology companies to emerge on the scene, started by focusing on mass-producing artemisinin to treat malaria. They expanded into bio-fuels, faced down several challenges, and came out of the bio-fuels hangover in a much better position – at least as far as their technical capabilities are concerned.
The Amyris team was forced to develop lots of bioengineering version 1.0 tools.
Today, they have the experience and capability to roll out a lot of projects, and their 2016 agreement with Ginkgo Bioworks shows that Amyris is interested expanding access to their now-sophisticated manufacturing capacity. They have made a great deal of progress in being able to iterate design, build, and test by automating their engineering processes.
Through those years of development and learning, Amyris experienced a few bumps in the road, resulting in a diaspora of talented people who are now taking what they learned there to the next level.
Tim Gardner is a pioneer in the field of synthetic biology and a former employee of Amyris. There, he cobbled together their quality systems from whatever software was available at the time. He left and founded Riffyn to build a design studio and research and development platform from scratch. It’s a system that enables quality by design. The software dramatically improves reproducibility. It’s analogous to six sigma across all manufacturing. (Six Sigma is a disciplined, data-driven approach and methodology for eliminating defects (driving toward six standard deviations between the mean and the nearest specification limit) in any process – from manufacturing to transactional and from product to service. (isixsigma.com) “Six Sigma is a quality program that, when all is said and done, improves your customer’s experience, lowers your costs, and builds better leaders. — Jack Welch)
Riffyn is a Github for biological manufacturing processes. It allows easy version tracking of processes and let’s companies or individuals take an R&D or manufacturing process that works in one place and transfer it to another.
This helps address tech transfer hiccups that frequently crop up during mergers and acquisitions. For example, Roche recently eliminated Genentech’s manufacturing in South San Francisco and now has to enable that capability in other locations. R&D will still be conducted at Genentech HQ, but the manufacturing will be done elsewhere.
How do you communicate the manufacturing process from HQ to wherever the product will actually get made? Currently, that is all done manually for biotech products.
Lots of companies are great at engineering bugs to produce a product but few are great at scaling production. They have to outsource that process. This is smart because manufacturing can be expensive.
However, in outsourcing, they can lose ownership of the manufacturing process. Bringing that process back in house requires the ability to wrangle automation and genetics at the same time, which brings us to the arrival of design for manufacturing in biotechnology.
Synthace’s Antha allows you to go from the whiteboard all the way to automated measurement and manufacturing. Antha gives users clear and complete instructions and allows them to execute on hardware from many vendors. It’s really an operating system that links the research laboratory to the manufacturing plant.
Synthace is working on drivers for everything from automated cell culture systems, to liquid handlers, to PCR machines, to mass spectrometers. And at the core of Antha is a “multifactorial design of experiments” philosophy that treats all the settings on all these instruments, as well as all the genetic and physiological features of engineered organisms, as parameters that can be rapidly optimized in parallel. (From the Synthace website: Antha represents a ground up re-imagining of how we work with biology. Fundamentally, it is about empowering us to focus on What we want to do rather than purely How we do it. This is accomplished via the Antha OS for biology, that brings all of the benefits of modern computing into the lab.)
Ultimately, this allows users to better manage manufacturing lines. It is biological engineering in the way you would hope it would be.
Software and Infrastructure Accelerate Biological Engineering
Having all this software in one place will make the engineering of biology and manufacturing scale-up much easier. Design the pathway, prototype, then design the manufacturing process. You can hand off your bug and processes to a manufacturing facility and they will boot it up and start producing.
So, with all this engineering infrastructure are your disposal, what are you going to make?
Next Up: Enzyme and Metabolic Pathway Design
The next major development that will bring distributed biological process closer to reality is the design of enzymes and pathways that can use local feedstocks to produce end products.
Standard synthetic chemistry has provided a zoo of molecules that are the building blocks of the modern economy. Many products today are possible only through properties of molecules that are entirely designed and manufactured by humans. Whether through plastics, coatings or catalysts, synthetic chemistry literally transforms our world.
But of all the materials we can theoretically imagine, synthetic chemistry can be used to manufacture only a fraction.
Enzymes, however, can manage feats of chemistry that provide access to a much larger number of potential materials.
DARPA has a project underway to extend this capability by employing novel combinations of enzymes to build a thousand materials that have never existed before. Moreover, after a century of effort, we have learned enough biochemistry to start designing new enzymes, with new capabilities, that expand even further the accessible gamut of the materials spectrum.
This has already been demonstrated at a small scale, and largely without access to the tools that companies like Riffyn and Synthace are building. Imagine what will be possible when all these capabilities are brought together.
In a few years we will have the ability to design enzymatic pathways that use the most economically viable feedstocks to make products for whatever markets you want to focus on.
Coupling pathway design to test, measurement, and prototyping, and then finally to manufacturing processes, will be very powerful economically.
Software + Infrastructure + Enzyme/Metabolic Pathway Design = The Future
Microbrewing teaches us that distributed biological manufacturing is not only possible, but also that it can compete against large, centralized manufacturing. And this is with a product that is basically water, and worth only a few dollars a liter.
In contrast, there are plenty of compounds worth tens, hundreds, or even thousands of dollars a liter that are now derived from a barrel of oil. When those products can be brewed the way beer is, then distributed biological manufacturing will work even better.
Now, if you have the ability to describe those organisms and manufacturing processes in software — using something like a combination of Riffyn and Antha — then you enable a new kind of business altogether. This will allow us to develop and version processes, communicate processes, and license processes.
We’ll see new companies that have the option to develop and license processes rather than only to manufacture products, which would bring biology closer to the way the rest of the economy works. This is only possible when you have the full bioengineering tool stack at your disposal.
How is this going to play out?
The early wins in biology are coming from embracing what biotechnology already does best: Building bugs that produce valuable molecules that can be grown at the scale with the flexibility of brewing beer.
At the moment, because it is early and the tools are still new a bit expensive, only large players operating in large markets can make effective use of those tools.
Zymergen, which has its own homegrown tool stack, is seeing enormous success in optimizing production pathways for its customers, who own microbes that already generate many billions in revenues from chemicals.
Over time, however, the technology will diffuse out into the larger bioengineering community, which will support an increasingly diverse array of biologically manufactured products.
Ultimately, the market will decide how any given product is produced, and at what scale. But we already know that biological manufacturing works, in that it can outcompete high-end petroleum products even at today’s prices. It seems likely that, as the technology matures, brewing will be the future of biomanufacturing, and where microbrewing of chemicals makes sense, that’s what people will do.
Eventually, you’ll be able to scale production to meet local demand, while generating a profit at whatever scale works in your market. This was the core of my distributed biological manufacturing hypothesis 15 years ago and it is starting to be realized.