Microbes are the most prolific and diverse group of organisms on the planet. These tiny creatures are also incredibly useful. Researchers and biotech entrepreneurs employ microbes to produce medicines, alternative proteins, sustainable materials, and so much more. But, so far, all these innovations have been made using relatively few microbe types. However, with new technologies and rapidly growing microbe “libraries,” many scientists are searching for which microbe will be the next to transform synthetic biology.
The Extreme Gold Standard
One of the most significant microbe discoveries in synthetic biology has been Thermus aquaticus, or Taq. This organism belongs to a class of lifeforms called extremophiles, so named for their ability to survive in some of the most extreme conditions on Earth. Taq happily makes its home in geothermal pools and deep-sea vents, which can reach temperatures of at least 160°F. This key trait—stability at high temperatures—has made Taq a centerpiece of polymerase chain reactions (PCR), one of the most critical processes in microbiology.
PCR, powered by the Taq polymerase enzyme, enables researchers to make millions to billions of copies of a DNA fragment for further analysis and use. Its applications are tremendous, particularly in disease detection. Today, it plays a critical role in real-time testing for COVID-19. In short, this heat-happy microbe has given rise to a multibillion-dollar industry.
But Taq polymerase wasn’t always the gold standard for microbiology, and its rise to prominence hints at a vast, unexplored microbial search space. Before its discovery in the 1970s, scientists used DNA polymerase from E. coli for their DNA amplification endeavors. E. coli is an extremely useful microbe. It’s versatile, hardy, and fast-growing. But while it may seem ubiquitous, E. coli can’t do everything.
“A lot of synthetic biology has been centered around the bread and butter E. coli saccharomyces… but there are millions of [microbial] species that haven’t been tackled,” says Kevin Solomon, P.h.D, assistant professor of agricultural and biological engineering at Purdue University. Continuing to rely on just a handful of microorganisms could limit synthetic biology’s potential.
When In Doubt, Ask Nature
Developing biofuels and biochemicals is one of the biggest problems open to synthetic biology improvements. Current methods for converting biomass to more immediately useful materials are not optimized. Nature, however, has been perfecting this process for billions of years. Solomon points to fungi, nature’s biomass-breakdown MVP, to inspire how synthetic processes can improve their efficiency and impact.
Fungi use a whole repertoire of enzymes to degrade organic material. “This suggests that one, [fungi] may have unique tricks that might be more efficient and, two, it’s not as simple as moving [these enzymes] into E.coli, which is historically what the [synthetic biology] field has tried to do,” says Solomon.
Exploring and mapping fungal enzymatic pathways and other metabolic processes to expand beyond E. coli could open numerous new doors in synthetic biology as Taq did for PCR. To be clear, it’s highly unlikely that E. coli will be replaced as a standard tool of discovery. But, as Solomon emphasizes, it’s not the only available option.
However, there is a significant gap between theorizing about new microorganisms and actually testing their capabilities. The level of testing needed to understand new microbes will generate tremendous amounts of data. But this data is only as useful if it can be screened effectively.
Finding the Breakthrough in the Data-stack
The last ten years have seen the cost of bioengineering tools drop dramatically. Sequencing the first human genome took over a decade and cost $2.7 billion. Now, with next-generation sequencing, researchers can sequence a human genome for less than $1,000 in a single day — the Moore’s Law curve in action for synthetic biology. While sequencing, synthesizing, and editing DNA has become relatively easy, critical high-volume efficacy testing and analysis tools are still inaccessible for many labs.
“Because of the scope, I think a lot of [those tools] are still out of reach for the average lab. Not only is the cost a barrier, but you also need high-throughput screens that can make use of them effectively,” says Solomon. He explains that the average lab may only have access to a functional screen, which is itself difficult to develop, while the alternative liquid handling automation systems can cost millions of dollars. “The biology has become super accessible. It’s the parts that support it that need to come down in price now,” he says.
This is not to say there aren’t any accessible breakthrough tools. Methods like Golden Gate cloning or sequencing through the Joint Genome Institute have been transformative at all levels of research, especially in academia. “If you want to sequence a bunch of organisms, JGI can do that for you, no problem. The hard part becomes the screen because that’s more application-specific,” Solomon remarks.
Calling Startups: There’s A Big Niche to Fill
How can synthetic biology eliminate the screening bottleneck to unlock the potential of novel organisms? One way is to completely skip screening a broad range of organisms and take a more targeted approach instead.
“I think there’s a market for a company that could systematically explore the vast diversity of [microbes] on Earth,” muses Solomon. Such an approach would be critical; half-joking, Solomon says that many enzymes used now are essentially “random strains that people found on the bottom of someone’s shoe.” Instead, he envisions a catalog of “all the weird organisms” and their properties, which could be licensed out to researchers.
“There are literally billions of species on this planet. There’s no reason why synthetic biology should be limited to E.coli and yeast and other emerging strains,” he projects. With such an expanded search space available, one of the few remaining questions is where the next transformative microbe may be found.
The Sleeping Beauty of Microbes
There’s a chance the next transformative microbe neighbors with Thermus aquaticus. Last year, a team of researchers led by the Japan Agency for Marine-Earth Science and Technology revived 100-million-year-old microbes from deep-sea sediment. Like Taq, these microbes thrive in nutrient-poor waters with very little oxygen and, according to the research team, possess a variety of metabolic functionalities.
How did these microbes survive in dormancy since the dinosaurs? What can we learn from their ancient metabolic methods? Could these be some of the organisms that help drive synthetic biology’s next leap forward?
The pace of discovery in synthetic biology is continuing to accelerate. Researchers and entrepreneurs are being empowered to tackle our planet’s most difficult challenges through biology. But to be successful, the synthetic biology space needs to fully explore its plethora of available options — out-of-the-box tools for out-of-the-box solutions to out-of-the-box problems. Could deep-sea microbes revolutionize therapeutics? Could unique algae transform carbon capture? Could an ancient organism be our next sustainable food source? The synthetic biology community has the chance to reshape its own future as the future of our planet.
Thank you to Fiona Mischel for additional research and reporting in this article. I’m the founder of SynBioBeta, and some of the companies that I write about are sponsors of the SynBioBeta conference and weekly digest.
Article originally published on Forbes https://www.forbes.com/sites/johncumbers/2021/02/01/the-unexplored-power-of-microbes/?sh=69fa09523f380