The crystal jelly, Aequorea Victoria, is a jellyfish commonly found on North America’s west coast. Thermus aquaticus is a thermophilic bacterium fond of Yellowstone National Park’s hot springs. Both organisms live in their aquatic environments, unaware of the huge biotechnology potential they hide in their genomes. In the early 1960s, Japanese researchers discovered the Green Fluorescent Protein, synbio’s most widely used reporter, in the crystal jelly. In the early 70s, researchers from the University of Cincinnati isolated the Taq polymerase from T. aquaticus, a thermostable enzyme that made Polymerase Chain Reaction possible to develop a few years later. Moreover, if not for the pioneering works of biodiversity explorers, molecular biology and synthetic biology would need to grow without PCR and fluorescent proteins.
It is unclear how many species exist now on Earth, as estimates range between 5.3 million and one trillion. The vast majority of these species remain unknown to science, let alone studied and characterized. We can, therefore, only imagine what biotechnology potential is hiding in various ecosystems around the world.
“I firmly believe that exploring the vast diversity of “extreme” isolates will expand our range of potential solutions for industrial applications,” said Associate Professor Dimitris Hatzinikolaou from the University of Athens, Greece. Hatzinikolaou’s lab is exploring extreme environments, such as microbes thriving near industrial waste streams, algae from lakes of varying salinity, and even thermophiles from the Santorini volcano. “Many of these strains catabolize feedstocks that 'normal' microbes cannot use, while others produce industrially relevant metabolites through unique pathways and genes,” Hatzinikolaou added.
Most synthetic biology and biotechnology companies focus on using only one or a very limited number of strains for their applications. This is not the case for Algal Bio, a Japanese startup using algae to produce ingredients for various industries. The company’s strength lies in its deep knowledge of algae and their diversity. “We have an extensive algae library, breeding technology, and advanced cultivation techniques,” said Masahiro Kida, head of International Business Development at Algal Bio. “We can screen the best package of algae strain and cultivation conditions for novel products and solutions in health, wellness, food, carbon neutral, bioplastics, and more.” Algal Bio has built a very unique algae biofoundry platform, and they combine this resource with a unique partnership-based business model. Their mission statement of “cultivating algae’s potential for a better future” highlights their focus on taking algal diversity to the market.
Many startups could benefit from exploring a variety of strains and gain access to unique adaptations, genes and pathways, and new compounds with novel properties. Unconventional strains can also help with more practical aspects of application development: freedom to operate from IP/patent constraints, microbes able to perform in industrially relevant conditions, strains less susceptible to contamination, and completely new application spaces. For example, doing microbial fermentation in spaceships seems next to impossible with current technology. But biofilms of robust, radiation-tolerant, and cold-resistant bacteria have a better chance of finding their way into future space colonies.
Despite the advantages, though, using non-model strains is not trivial. Kida mentioned several challenges around maintaining and using a large strain collection, including costs, regulatory challenges, and data management. Kida’s advice to small synbio companies is to focus on a small strain set: “A limited number of strains makes it easier to maintain consistent and high standards of quality. When dealing with a large number, the risk of fluctuations and variations in quality increases.” Hatzinikolaou echoes the same sentiment: “I believe there should be a good reason why to engage in a non-model organism. Many of them have growth needs that are not known in their entirety, and molecular tools might need to be developed at a significant cost.”
However, using a variety of strains and discovering proteins in remote ecosystems is not the only way to harness biodiversity for advancing synthetic biology. Basecamp Research, a UK startup, uses biodiversity as a learning resource. The company then applies these lessons to protein design, using a combination of data mining and machine learning tools. “We are looking at biodiversity with a design lens on it. We try to understand the design language and principles and make new synthetic protein designs,” explained Glen Gowers, co-founder at Basecamp Research.
When asked to explain in more detail how they use information from nature to solve protein design issues, Gowers used an analogy from ChatGPT, explaining that the large language models are trained using a limited subset of articles and texts. Thus, they “learn” the rules of language and can participate in conversations about topics totally new to them. Basecamp has partnered with 23 countries on three continents to collect samples, sequence them, and create datasets that encapsulate genetic sequences, environmental information, and microbial community interactions. They then train their algorithm to answer the following question: how would biology adapt to a situation never encountered in nature, imposed by human protein designers? Basecamp recently announced its collaboration with another of the UK’s most innovative startups, Colorifix. The two startups will join forces to revolutionize the way clothing textiles are made. Basecamp secured $20M Series A funding last year, confirming that biodiversity makes good business.
The narrative of how biodiversity and synthetic biology interact has evolved over the years. Initially, natural ecosystems were seen as a field of discovery: new genes, new small molecules that can cure disease, and new organisms that can perform better. The conversation shifted to using synbio for conservation. Synthetic biology can act as a vessel to store biodiversity information before it withers due to habitat loss and climate change. Now, a new narrative arises where synbio learns by nature and gets inspired for new design concepts. One thing is sure. As synthetic biology grows, we must create a new symbiotic relationship with natural habitats. Synthetic biologists need to understand how biodiversity can guide and advance their work; they also need to champion the protection of natural resources and let biology continue to be amazing with the ingenuity and beauty it provides humankind.