Synthetic Biology - The ticket to a Sustainable Future

A group of scientists once created a genetically modified species in the lab which accidentally escaped the premises and created havoc. Sounds familiar? Yes, it is the plot from the movie ‘Jurassic World’, or it could also be the plot from any other science fiction movie of our times. While movie makers have always flirted with the idea of genetically modified organisms and piqued the imagination of many, scientists across the world have been able to work on developing technologies which would make many of these ideas into reality. From the early discovery of restriction enzymes and other cloning techniques to the advancements in genomics and sequencing technologies, to the development of engineering techniques and finally leading up to the use of computational logics, we have really come a long way. These advances over the last 50 years have defined what we now know as the field of ‘synthetic biology’.

So, what is synthetic biology?

The term synthetic biology was coined by Polish geneticist Waclaw Szybalski in 1974 while working on genetic engineering techniques. While several definitions have floated around, simply put, it is the engineering of natural biologic systems such as bacteria, yeasts and fungi, plants and animals to produce the desired products. There are two broad ways to do this: (A) the design and construction of new biological parts, devices and systems, and (B) the re-design of existing, natural biological systems for useful purposes.

How has the market evolved?

Nature, in 2010, published an article articulating the key challenges with synthetic biology named ‘Five Hard Truths for Synthetic Biology’. The year marked the end of the first decade of synthetic biology. In the early 2000s, researchers were slowly gaining the ability to read nature and the genetic makeup responsible for producing specific molecules quickly and at a low cost through breakthroughs in DNA sequencing and solid-state spectroscopy. Initial ideas on synthetic biology were taking shape: characterize the genetic sequences that perform needed functions, identify the ‘parts’, combine the parts into devices to achieve more complex functions, then insert the devices into cells. The first generation of synthetic biology from 2000 to 2010 saw researchers develop a few of these parts and circuits which were published in the Registry of Standard Biological Parts and OpenWetWare. However, as the complexity and unpredictability of these circuits increased, it became difficult to design them in-vitro due to lack of understanding and characterization of the parts and the inherent lack of efficient engineering and designing capabilities. There were three key challenges: reliability, standardization, and automation of the design.

This period also saw several companies emerge with the United States taking the lead. The first-generation of synthetic biology companies from the early 2000s such as Evolva and Amyris were full stack companies focusing on a singular product line such as biofuels. The promise of producing environmentally friendly fuels capable of replacing fossil fuels looked attractive on the face of it. However, these companies found it difficult to scale as they couldn’t o produce cost-competitive fuels. After a while, they pivoted to making high value chemicals. Several companies similarly failed in the pursuit of doing it all by themselves — designing the DNA, engineering the organisms, fermentation and manufacturing and downstream processing. It was time to assemble The Avengers.

And the Avengers did come together. The next decade (2010–2020) saw the emergence of companies with platform technologies offering ‘synthetic biology as a service’. These include companies such as Ginkgo Bioworks (started a bit earlier in 2008), Zymergen, and Twist Bioscience which have all found success by selling engineered organisms and nucleic acids for multiple applications. A few companies such as Synthace and Leselagen Biotechnology built AI-based software to efficiently design DNA/RNA sequences. Divide and conquer was the new rule book to play by.

With companies having specific focus areas, technology development intensified and grew at a rapid pace leading to key breakthroughs. A design-build-test-learn cycle has been put in place: computer-aided nucleotide design, synthesis, and testing of DNA/RNA and engineered organisms using technologies such as CRISPR, pooled oligo synthesis, and Next Generation Sequencing (NGS) and microfluidic devices and finally storing the data and training machine learning algorithms to fasten the design process. All of this has eventually led to two key advancements:

1. A significant drop in the cost of DNA synthesis and sequencing
2. Faster designing of genomic sequences leading to a significant increase in the number of synthetic genomes.

The synthetic biology market has seen more than a threefold increase in the number of companies from the first to the second decade. From its use in biofuels to agricultural seeds, the market has expanded into other fields. Currently, synthetic biology is being used across healthcare, food products, agriculture, industrial chemicals, biofuels, and consumer products. Companies such as Gingko Bioworks and Zymergen are transforming these industries by creating an ecosystem of partners and customers, making them ecosystem engineers. For example, Zymergen has partnered with Sumimoto Chemical to develop a biopolymer film called ‘Hyaline’.

Investor sentiments:

Stewart Brand, the well-known editor of the Whole Earth Catalog once said in a Ted interview in 2013-

Tech leaders of the last century including Bill Gates, Peter Thiel, Marc Andreesen, Eric Schmidt, Vinod Khosla, and many others have echoed this sentiment. Investors see a lot of parallels between the computer revolution of the 1970s and the revolution happening in the field of synthetic biology since 2010. The undeniable potential of synthetic biology to impact multiple markets driven by the decrease in costs of DNA sequencing and synthesis has stirred the private funding ecosystem into action. These tech leaders have led investments into major synthetic biology companies such as Zymergen, Gingko Bioworks, Twist Bioscience, and many others through their venture capital funds which include Founders Fund, Andreesen Horowitz, Lux Capital, General Catalyst, and many others. From a meager $100 million in 2010, investments topped $18 billion in 2021. This figure is quite bullish considering there are still few commercial products in the market as of now.

Investors are betting hard and long on the potential of synthetic biology to disrupt markets and create a lasting change in the world. Investments have increased more than 10x since 2010, coinciding with critical technological milestones between 2010–2020. Second generation companies providing ‘synthetic biology as a service’ such as Gingko Bioworks, Twist Bioscience and Zymergen, who saw several hundred million dollars in private investments, have gone public. The exit valuations (for early investors) for these companies were more than 100 times their annual revenues.

The precedents of success have spurred investors to double down on their investments and shift towards applications of synthetic biology. Investments in healthcare and food companies using synthetic biology have exploded. In 2021, they saw $7.4 billion and $3.4 billion respectively — figures equivalent to the total amount of investments in these fields over the last decade. Investors expect the next decade to provide greater breakthroughs in product commercialization.

Governments are also showing interest in synthetic biology. The European Union invested around 450 million euros into synthetic biology between 2004–2013 through multiple policies and initiatives. The United Kingdom has invested more than 300 million pounds while China has put in more than 200 million dollars in synthetic biology between 2011–2015. The United States has already invested more than a billion dollars into synthetic biology research. These investments have been driven by climate change concerns rising from excessive use of fossil fuel-based products. Synthetic biology offers a sustainable route to produce industrial chemicals, food, healthcare, and agricultural products.

In India, the field of synthetic biology is at a very nascent stage. There are several research institutes, including the IISERs, IITs, BITS, IIScs, MITADT, working on synthetic biology techniques and products. The first Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based product from India was commercialized in 2020. The technique is used for targeted gene editing. Known as ‘FELUDA’, the COVID-19 detection product was developed by the Council of Scientific and Industrial Research’s Institute of Genomics and Integrative Biology (CSIR-IGIB) along with the TATA Group.

Apart from larger conglomerates such as Reliance Industries, which are looking at synthetic biology to improve their existing product line and develop more environmentally friendly ones, much of the investments in the field have been in the form of grants from government organizations such as BIRAC. Private funding from VCs has remained low. Open-access collaboration and access to resources have also remained a huge hurdle. This has limited the growth of the market.

The future opportunities and challenges:

The market for synthetic biology is at a tipping point as we enter the third decade of the industry. Based on the pipeline of products under development across the world, a Mckinsey report estimates an economic impact of more than $4 trillion a year over the next two decades. Technological breakthroughs over the last decade coupled with the design-build-test-learn methodology have made cell line engineering much faster and easier. The next decade will be targeted towards developing a standardized set of bio-design tools to be used across the supply chain. Opportunities will also emerge in designing robust AI/ML-based tools and automation for even faster gene design and synthesis.

While a few products were launched in the market during the fag end of the last decade, it was just a drop in the ocean. Moving products from the lab to the market is challenging and there are a few other pieces of the puzzle that need attention:

1. Tech-transfer challenges: typically, technology transfer entails an iterative process optimization of the lab results at the industrial scale. Companies face challenges in cell line stability, economics and purification of the product. Producing similar yields at the industrial scale as seen in the lab is always a challenge.
2. Creating a robust supply chain: for synthetic biology products to move from the lab to the market, it is important to create an integrated and competitive supply chain. After all, a shift from a chemical-based industry to a bio-industry cannot happen without all the stakeholders in the industry playing their part. There are four key issues in the synthetic biology supply chain which need to be addressed:
   a) Lack of specialization: synthetic biology currently has larger organizations that are trying to vertically integrate and perform all functions from engineering the organisms to the final downstream processing of the product. This is difficult to achieve and is one of the main reasons for the struggles of these companies in the market. The market will have to move towards an ecosystem approach with specialized organizations taking care of different stages of product development and commercialization.
   b) Lack of standardization: industry standards go a long way in ensuring uniformity in the designing and manufacturing processes, indirectly maintaining the quality of the products. Despite the work done by organizations such as BSI and NIST, the synthetic biology market is a long way away from establishing standards for recording and analysis of raw R&D data, data management, automated workflows, commercial manufacturing, and regulatory approvals. Going forward, the market will need to build these standards such as GLPs and ISOs to successfully scale the product.
   c) Scaling up production: currently, contract manufacturing organizations (CMO) are not fully developed to handle the complexities involved in the management of synthetic biology products. These organizations are struggling with high upfront costs, lower margins, and difficulties with variabilities in the feedstock. The market will need CMOs that can produce a range of synthetic biology products using one set of assets.
   d) Downstream processing: downstream processing takes up more than 60–70% of the total manufacturing cost. Most synthetic biology companies lack the expertise to purify the products at a larger scale. The market will require specialized downstream companies to take care of the product purification steps.
3. Improving the market regulations: the United Nations Convention on Biological Diversity (CBD) is the primary body overseeing the regulatory aspects of synthetic biology. Currently, there are two major subsidiary agreements in place under the CBD’s guidance: The Cartagena Protocol on biosafety of living modified organisms (2000) and the Nagoya Protocol on access and sharing of genetic resources (2011). Apart from these, there are several national policies and regulations being formulated on the use of synthetic biology. The regulations vary depending on the intended applications from human health to food and agriculture. For example, while Brazil is a highly regulated market when it comes to gene editing applications in human health, the country has been more favorable of its use in food and agriculture. Regulations also vary depending on the type of editing being performed. Typically, site-directed Nuclease (SND) 1 and 2 types of mutations that involve gene deletion and overexpression are exempt from the GMO category, while SND3 involving the addition of foreign DNA is being considered under the GMO purview.

In India, there is a strong apprehension toward the use of genetically modified organisms in the country, as seen by the fact that there is no GM food crop approved for commercial cultivation. The only cash crop which has seen the success of advanced seeds is Cotton. The Department of Biotechnology, in February 2022 released a foresight paper on synthetic biology. This document highlights the policy and regulatory aspects of the field across the world and lays the groundwork for a future policy on synthetic biology.

As we enter the third decade of synthetic biology, the world has a chance to rethink its future. Synthetic biology can drive us towards a more equitable, sustainable, and inclusive future by replacing the dependence on chemical and fossil fuel-based products. While the demand for sustainable products has increased, the market is striving toward building cost-competitive products using advanced synthetic biology tools. The next decade is expected to open up opportunities in designing computational techniques for genomics, standardizing the tools for organism engineering and scale up and commercializing the products.

We are not far from the day that synthetic biology becomes a norm, not just a choice. A world where humans truly work with nature to build the future!

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