By S Ramadorai, Raman Srinivasan & S Shivaramakrishna

In the introductory essay (bit.ly/3p6pqwZ), we shared a summary of the intellectual history of this new scientific discipline, synthetic biology. In this article, we take a look at the three generations of synthetic biology startups and examine how these new companies herald 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 over the past decades. With a deep understanding of genetics, metabolic pathways, and artificial intelligence, synthetic biologists are now able to refactor microbes to create new molecules needed for truly flexible films for digital screens. Machine learning algorithms trained on nature’s vast repository help select specific microbes to function like tiny factories.

Three generations of synthetic biology start-ups:
In recent weeks, two American synbio startups, Zymergen and Ginkgo, have gone public, recalling the craze around the first generation of synthetic biology startups ten years ago. Evolva, a young synbio start-up focused on flavors, ingredients and materials, went public in December 2009. It was followed in September 2010 by Amyris, a well-funded start-up focused on biofuels. However, the markets remained lukewarm for the first generation of synthetic biology companies. We believe that the spectacular success of Zymergen and Ginkgo signals the advent of synthetic biology.

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

Scientists have identified microbes that could produce energy-rich fuels in copious amounts when fed 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 have come up with ways to purify and treat 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 focused on a single application, eg biofuels, with a large market and sought to integrate vertically. They imitated the oil barons of old. Naturally, these companies were heavy on capital expenditures and inherently risky. However, given that much of the early history of synthetic biology was propelled by US government mandates, whether through military or energy research, there appears to have been sufficient funding. to drive the first generation of businesses, at least initially.

Naturally, when the expected demand for the promised products did not materialize, businesses struggled.
To unbiased observers, early synthetic biology startups often appeared to be problem-seeking solutions. Saffron is one of the most expensive spices in the world. The stigma, which is part of the flower of Crocus sativus, is what makes up the spice. The flowers are picked by hand, dried and the desirable parts separated by hand. It has always been a labor intensive crop and difficult to cultivate on a large scale as well.

Saffron is the key compound in saffron that makes saffron. Synthetic biologists at the Chennai laboratory of one of the first synthetic biology companies have found ways to get E. coli to produce saffron. Likewise, other companies have acquired patents to make sandalene, a key component of sandalwood oil and a valuable ingredient in perfumes with its familiar sweet, sweet woody and animal balsamic scent.

Traditionally, perfumers distill the heartwood of mature sandalwood trees to obtain the scented sandalwood oil, but relentless exploitation has led to the near extinction of natural sandalwood. And it turned out to be difficult to grow in the plantations. The chemical synthesis of sandalene and other aromatic compounds in sandalwood oil has proven difficult. Some of the early synbio startups developed effective synthetic biology pathways to safranal and sandalene.

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

The infected wood is shredded and the agar is extracted. Also in the case of agarwood, the basic five-step process of the synthetic biology path applies. The first step is to identify the key molecule contributing to the “essence” of agarwood scent. The second step is to “read” the genetic code of nature which is responsible for making this molecule. The third step is to “write” that code or sequence into a microbial workhorse, say, regular 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 them as needed.

Sadly, neither green fuels nor exotic luxury ingredients have proven to be enough to fuel the first wave of synthetic biology start-ups. In the next article, we’ll see how second- and third-generation synbio start-ups retool for success.

Ramadorai is the former vice president, TCS, Srinivasan is chief, TCS Ignite and Shivaramakrisha is researcher, TCS