Synthetic Biology | The first-gen start-ups: Flying high on fragrance

June 01, 2021 4:30 AM

The first-generation synbio companies were "full stack", i.e., they focussed on a single application with a large market and sought to vertically integrate

We believe that the spectacular success of Zymergen and Ginkgo signals the coming of age of synthetic biology.

By S Ramadorai, Raman Srinivasan & S Shivaramakrishna

In the introductory essay (bit.ly/3p6pqwZ), we shared a summary intellectual history of this newest scientific discipline, synthetic biology. In this article, we look at the three generations of synthetic biology start-ups and examine how these new companies are heralding a fifth industrial revolution. Biology is technology.

Life is code. The genetic code can be quickly read, edited, and written using a variety of tools developed in the last few decades. Using a deep understanding of genetics, metabolic pathways, and artificial intelligence, synthetic biologists are now able to refactor microbes to make novel molecules needed for truly flexible films for digital displays. Machine learning algorithms trained on nature’s vast repository help select specific microbes to function as tiny factories.

Three generations of synthetic biology start-ups:
Within the last few weeks two American synbio startups, Zymergen and Ginkgo, have gone public, recalling the enthusiasm around the first generation of synthetic biology start-ups about ten years ago. Evolva, an early synbio start-up focussed on flavours, ingredients and materials went public in December 2009. It was followed in September 2010 by Amyris, a well-funded start-up focussed on biofuels. However, the markets remained lukewarm to the first generation of synthetic biology companies. We believe that the spectacular success of Zymergen and Ginkgo signals the coming of age of synthetic biology.

First generation:
Full stack approach
The first generation of synthetic biology start-ups aimed for the skies, literally. Companies like Amyris sought to produce biofuels for aircrafts. Gobar gas is what comes to our minds when we hear the term biofuel. But, the pioneers of synthetic biology dreamt of a brave green world where jet engines flew high on chemicals normally found in orange and apple peels.

Scientists identified microbes that could produce energy-rich fuels in copious amounts when fed with cheap sugar in giant fermenters under the right conditions. Synthetic biologists then devised ways to precisely engineer microbes to produce these specific energy-dense molecules. Finally, engineers developed ways to purify and process the output of these microbes as plug-in replacements for aviation fuel.

The first generation synbio companies were, to borrow an analogy from the tech world, full stack. They focussed on a single application, for example, biofuel, with a large market and sought to vertically integrate. They emulated the oil barons of yore. Naturally, these ventures were capex-heavy and inherently risky. However, given that much of the early history of synthetic biology was propelled by US government mandates, either through military or energy research, there appears to have been enough funding to drive the first generation of companies, at least in the early days.

Naturally, when the anticipated demand for the promised products failed to materialise, companies struggled.
To dispassionate observers, the early synthetic biology startups often appeared to be solutions in search of problems. Saffron is among the most expensive spices in the world. The stigma, part of the flower of Crocus sativus, is what constitutes the spice. The flowers are manually gathered, dried, and the desirable parts separated by hand. It has historically been a labour-intensive crop, and one difficult to grow at scale as well.

Saffranal is the key compound in saffron that makes saffron saffron. Synthetic biologists in the Chennai lab of an early synthetic biology company figured out ways to get E. coli to produce saffranal. Similarly, other companies acquired patents to make santalene, a key component of sandalwood oil and a valuable ingredient in perfumes with its familiar soft, sweet-woody and animal-balsamic odour.

Traditionally, perfumers distil the heartwood of mature sandalwood trees to obtain the fragrant sandalwood oil, but relentless exploitation has led to the near-extinction of natural sandalwood. And it has proved to be difficult to cultivate in plantations. The chemical synthesis of santalene and other aromatic compounds in sandalwood oil have proved to be challenging. Some of the early synbio startups developed efficient, synthetic biology routes to saffranal and santalene.

Agarwood trees produce agar/aguru (a fragrant resin) used for agarbathis in a most unusual way. For example, they are now being commercially cultivated in fresh agarwood plantations in Hojai district of Assam. Once the trees reach a certain level of maturity, they are actually infected with a fungus and bandaged. As the fungus attacks the tree, it turns dark in color and produces the musty aroma of agar.

The infected wood is chipped and the agar is extracted. In the case of agarwood also, the basic five step process of synthetic biology route applies. Step one is to identify the key molecule contributing to the “essence” of agarwood fragrance. Step two is to “read” nature’s genetic code that is responsible for making this molecule. Step three is to “write” this code or sequence into a microbial workhorse, say, the common baker’s yeast. Step 4 is to feed the yeast with the right sugars in a fermenter. The fifth and final step is to collect the valuable molecules from the fermenter and process it as required.

Unfortunately, neither green jet fuels nor exotic luxury ingredients proved to be sufficient to nurture the first wave of synthetic biology start-ups. In the next article, we will look at how the second and third generation synbio start-ups are retooling to succeed.

Ramadorai is former vice-chairman, TCS, Srinivasan is head, TCS Ignite, and Shivaramakrisha is researcher, TCS

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