Industrial Romanticism & The Third Wave of Synthetic Biology

On August 9th, 2023, the #syntheticbiology pioneer Amyris?announced its voluntary filing for Chapter 11/Bankruptcy . I think this is a very important moment for the industry as it officially sanctions the end of an era, and (I hope) the beginning of a new one for the industry, and more in general for the transition of our industrial backbone from an exploitative to generative paradigm.

There is a lot that should be said, and I will do it in future posts, about the absolute inadequacy of the current #vcfunding model to fund this kind of industrial endeavor. I have written extensively about it in the past , and much of it still holds true. Luckily, there are new models emerging, that are showing how this can, and should, be done (e.g. the?Vargas ?model with Northvolt and H2GreenSteel). Furthermore, there are more fundamental issues with the current VC model that are well addressed by Kyle Harrison in his post on?The Institutionalised Belief in The Greater Fool .

Similarly, a lot should be said about the mismanagement that happened at Amyris over the years, but, as mentioned above, this is material for a different post…

Hopefully, this moment is recognized for what it is, i.e. the official end of an era, and the beginning of a new (successful) one, and is not perceived instead as the confirmation that, ultimately, the industry is not economically viable, given not only Amyris, but all the other companies that are currently struggling or have failed already (Zymergen, Bolt Threads just to mention a few…) and also given how nervous investors are starting to get about the industry…

Writing off synthetic biology now would be similar to writing off the internet after the .com crash.

It is important to put things in perspective, to understand the current developments. What we are experiencing right now is basically the end of the first two waves of synthetic biology, and the beginning of a new, third one, which is already underway and is pointing to the establishment of the industry, with a very different setup and attitude.

The first wave was triggered by the biofuel boom, but the development of the oil price and the economics of the industry busted the hype and let the bubble explode. Amyris was born during this phase, it managed to survive it and join the next wave.

The second wave for the industry was the “brute force” phase, epitomized by Ginkgo Bioworks and Zymergen, and was built on the fallacious belief that biology is just a “code” (DNA) and that we can “engineer” nature through simple brute force, by trying harder and harder (e.g. High Throughput Screening) till we find a solution. Eventually, the market has come to the conclusion that this approach does not work, as almost nobody has been able to make money with it so far. Zymergen collapsed, and Ginkgo is far from the height of the valuation it used to have and is moving more and more toward bio-pharma, which is governed by very different economics.

The bankruptcy of Amyris has now simply put a definitive seal to the non-viability of this approach.

But the good news is that we are now entering a new, third wave of synthetic biology, where the industry is starting (slowly) to realize that we cannot engineer nature, that a reductionist approach as in the second wave simply does not work when confronted with the immense intrinsic complexity of biology and the only way to be successfully operating in the space is to acknowledge the complexity of Nature and to define a strategy to cope with its complexity. This new approach is very often based on data, and the capacity to make sense of them (with AI, but not only), as pointed out by?George Darrah at SystemIQ .

What is emerging, is that there are fundamentally three possible different ways to cope with Nature’s complexity, and each requires a very different approach, a different strategic setup, and different economics.

• Option 1: Stripping the complexity out of nature through Cell Free Biology. This is the route taken by?Solugen ?and?Enginzyme , to mention a few. The core question is the range of applications for which this approach is economically viable, and also its industrial translation, but the current success of Solugen indicates that this is most likely a viable path forward
• Option 2: Exploring and looking in nature for ready-to-use organisms and conditions, that have already been trained by Nature to do what we want them to do, usually over millennia if not millions of years. Once found, then they can be scaled industrially. This is the route taken by?MicroBryre ?and also by?Wild Microbes , but also by?SQIM ,?Nature’s Fynd ?and?Arkeon , just to mention a few.
• Option 3: Embrace Nature’s complexity by designing organisms and developing instruments to let Nature “co-design” the organisms, tapping into billion years of evolution, by identifying the best solutions and fully exploring the broadest possible option space, subsequent to the genetic modifications, in an efficient manner. Most importantly, it is essential that the co-design together with Nature happens across all scales, from the lab down to the manufacturing environment, else it will not be possible to bring it to fruition with the production of the products developed in the lab (as it has been the case in the second wave). Companies like?Officinae Bio ?(disclosure: I am an investor) and?Melonfrost ?are best positioned to co-design the organisms together with Nature, through either their probabilistic approach, complexity background, and systemic approach or by leveraging evolution.

Of the three different options, Option 3 is probably the most challenging route, and therefore it should be used only for things that cannot be achieved with the other options (and with green chemistry) and where the products have a TEA (Techno-Economical Analysis) that justifies them. But, at the same time, it is also the one with the biggest potential.

Arsenale BioYards, the company I co-founded, has fully embraced Option 3 and is building the industrial infrastructure to enable companies, and product designers, to co-design with Nature across scales, or, better said, to let them design at scale directly, in the conditions at which the organism is going to operate in the manufacturing environment. This step is fundamental, as it brings forward the industrial conditions and embeds them in the scientific process, morphing it into an industrial one from the very first minute of the process design. The big advantage is that, if done properly, this will lead to much better TEAs because of the broader option space explored and, with it, the identification of better solutions, faster and at a lower cost point.

What we are doing with Arsenale BioYards, is what I?previously called ?“Industrial Romanticism”, in which we are building a new industrial infrastructure, which relies on Nature and co-designing with it, to enable the shift from an extractive to a generative industrial paradigm. It is, to a certain extent, the revenge of the Romantics, who in the 19th century were against the Industrial Revolution which was antagonizing Nature by relying on mechanical machines. With Option 3 and what Arsenale BioYards is building, we are now putting Nature back at the center of this new generative Industrial Revolution, which I like to describe as Industrial Romanticism.

Overtime, the three options will most likely converge, in which processes/products from Option 2 and 3 will be able to be used as precursors for Option 1 (Cell Free Biology), and organisms identified with Option 2 will be characterized, “domesticated” or simply “evolved” so to be able to leverage the infrastructure built for option 3 to produce (new or better) products.

While in the post I implicitly focused on “industrial” synthetic biology, down the line the developments outlined above are going also to impact the whole life sciences field, particularly on the manufacturing side, potentially bringing a very different cost structure into play for life sciences as well.

Of course, I am biased, given my role with Arsenale BioYards, but the one thing I can state with confidence is that it is?NOT?a continuation of the brute force approach, married with the incumbent manufacturing environment that is going to bring us the bio-revolution we have been waiting since the first and second wave of synthetic biology. Despite all of the discussions around the claimed lack of capacity, more of the same is not going to be the solution.

This brings me to the title of this post: I do believe that Industrial Romanticism and the third wave of synthetic biology are the solutions we were waiting for and that this new phase of Synthetic Biology is the one that eventually will manage to deliver against its potential.