Key Points
Synthetic biology provides a powerful way to test hypotheses about life on early Earth.
Engineered microbes are helping scientists trace the origins of fundamental biological processes, including nitrogen fixation, and uncover how life and Earth co-evolved over billions of years.
Experimental evolution systems, such as snowflake yeast, are revealing how multicellularity can emerge from single-celled organisms and may help establish general rules governing this major evolutionary transition.
By modifying modern microbes and rebuilding aspects of ancient biology, synthetic biologists are exposing critical gaps in our understanding of life's metabolism, evolution and origins.
Microbes are pioneers of the planet. They evolved over millennia from the primordial precursors of ancient Earth, the starting point for the preponderance of life as we know it.
The question is: how?
Once purely existential, the query into how life emerged has moved into the world of experimentation. At the crux of these advancements is synthetic biology, the application of standardized engineering techniques to generate organisms or biological systems with novel or specialized functions. Scientists can insert DNA synthesized in the lab into an organism's genome, bestowing it with new capabilities (e.g., the ability to make drugs or biofuels). The integrated DNA may encode a novel gene, or one found in another organism; researchers have even synthesized entire microbial genomes from scratch.
Now, they're using synthetic biology to interrogate ancient microbial processes and phenomena. Their findings have the potential to revolutionize how we think about Earth's earliest residents-and those that exist today.
Life and Earth Evolve Together
According to Betül Kaçar, Ph.D., a professor in the Department of Bacteriology at University of Wisconsin-Madison and Director of the NASA MUSE astrobiology research consortium, life as we know it has 3 key features: a genome, a metabolic network and membrane-bound compartmentalization.
These components are influenced by and influence the environments in which they interact and evolve. When thinking about the origins of life some 4 billion years ago, this is a particularly prescient point.
"Life evolves in tandem with the planet," Kaçar said, highlighting that evolution of ancient life was shaped by the geo- and biochemical state of the planet, while also transforming it (e.g., the evolution of oxygenic photosynthesis changed Earth from an anoxic to oxic environment). If we can understand the metabolic processes of ancient microbes, we can better understand the early planet, and vice versa.
Kaçar is interested in clarifying and contextualizing these connections. Her lab uses synthetic biology tools to reconstruct ancient microbial genes inferred from modern sequence data and statistical and evolutionary modeling and then inserts the DNA into living microbes. "[We then] compare and contrast the phenotypic outputs of what we engineered with the evidence preserved in the rock records," she said.
Reconstructing Ancient Microbial Metabolism
Take nitrogen fixation-the process in which microbes convert atmospheric nitrogen into biologically usable compounds, like ammonia-as an example. Data from ancient rock samples suggest nitrogen fixation emerged roughly 3 billion years ago. At the heart of this metabolism is the enzyme nitrogenase, and at the heart of many nitrogenases is a metal cofactor called molybdenum (Mo).
In a recent study, Kaçar's team reconstructed a library of synthetic ancestral nitrogenase genes spanning over 2 billion years of evolutionary history and inserted them into the bacterium Azotobacter vinelandii, a model for nitrogen fixation. They then measured cellular nitrogen isotope fractionation (a key step of nitrogen metabolism in which the 2 N atoms that make up atmospheric nitrogen are split apart).
Notably, the fractionation values were within the range exhibited by modern microbes. While it's impossible to conclude that the reconstructed enzymes behaved in A. vinelandii exactly how they did in their ancestral hosts, the results do suggest strong conservation of nitrogen isotope signatures produced by nitrogenases over time. Paired with data from ancient rocks, the findings also suggest a link between the early nitrogen isotope record and biological nitrogenase activity.
Kaçar emphasized that the latest findings on the presence of Mo-dependent nitrogenases so early is curious, given geochemical evidence that Mo was extremely limited on young Earth. One would expect that nitrogenase used different, more prevalent metals (e.g., iron) in the beginning, with Mo being incorporated once it increased in abundance in later eons. And yet, "the environment alone didn't necessarily dictate what this enzyme relied upon." Instead, factors beyond resource allocation may have influenced the evolution of key metabolic systems. This research poses new questions about microbial and enzymatic evolution that synthetic biology can help answer.
Reconstructing ancient microbial metabolism can ultimately crystallize the interplay between life and Earth in their earliest days, refining our understanding of the evolutionary processes that got us to where we are today.
"No one's claiming that we can recreate early life [exactly]," Kaçar noted, "but this gives us a tremendous starting point for investigating how ancient biological systems may have functioned."
Probing the Origins of Multicellularity
The power of synthetic biology to lift the veil on life's origins extends to other fundamental questions, too, including doozies like "how did multicellularity emerge?"
Multicellularity is a hallmark of modern life (think plants, animals, people), but its origin story is an open question. "By leveraging synthetic biology, I think we are at the cusp of generating a general theory of multicellularity that doesn't just understand how it could have arisen, but [also] understands the processes and dynamics and rules through which it does arise," said William Ratcliff, Ph.D., a professor in the School of Biological Sciences and Director of the Interdisciplinary Graduate Research Program in Quantitative Sciences at Georgia Tech.
Multicellularity has evolved more than 50 times across the Tree of Life. The path from unicellular to multicellular meanders through 3 stages. First, cells must adhere or aggregate to form multicellular groups (microbes already do this all the time). Multicellular individuals arise when natural selection begins operating at the group level rather than at the level of individual cells. In the final stage, multicellular individuals may evolve into organisms in which cells are functionally integrated and specialized.
"Adaptations at the group level eventually transform groups into functionally interdependent communities where the former individuals, the cells, can no longer function on their own," Ratcliff explained.
Snowflake Yeast and Synthetic Biology
How these transformations play out has been a key focus of Ratcliff's lab. For the past 8 years, his team has been exploring the emergence of multicellularity in real-time via the Multicellularity Long Term Evolution Experiment (MuLTEE).
The experiment uses snowflake yeast, a strain of Saccharomyces cerevisiae with a single mutation that keeps daughter cells attached after cell division, forming branching clusters. Every day, Ratcliff's team identifies isolates that settle rapidly in liquid media, thus selecting for large multicellular bunches.
Over more than 10,000 generations, the MuLTEE has provided insights into the evolutionary stages of multicellularity. For example, the yeast have evolved from single fragile cells to large groups visible to the naked eye that are as strong as wood. There is even some evidence of cellular differentiation and specialization. 
Ratcliff emphasizes that additional synthetic experimentation in snowflake yeast and other systems can bring still-unclear aspects of multicellularity-such as the genetic underpinnings of cellular division of labor, or the effects of environmental factors (e.g., oxygen levels) on the origins of multicellularity and organism size-into sharper relief.
Based on data from his lab and others, Ratcliff posits that the transition from unicellular to multicellular may not be as intrinsically difficult as we once thought. That is, the capacity to progress through the evolutionary stages of multicellularity may be a common feature of life; if and how that progress happens depends on pressures and features of the environment in which the organism is evolving.
"There's nothing special about any lineage that makes the transition to multicellularity. Every lineage has what it takes to do this. That's the hypothesis," he said. "We can test this through synthetic biology tools and interrogating the Tree of Life."
What Don't We Understand About Life Today?
As researchers make these interrogations about early microbial life, they're also finding just how little is known about the organisms that exist today. Disrupting or modifying a system can reveal aspects of biology that scientists didn't even know to wonder about, while also providing a foundation for biotechnological innovations.
"There's still some fundamental things about how life works we just don't understand, and that's where I think synthetic biology is really powerful in helping us figure some of those things out," noted Jeffrey Gralnick, Ph.D., Distinguished McKnight University Professor of Plant and Microbial Biology and Associate Dean for Faculty and Research at the University of Minnesota College of Biological Sciences.
He pointed to work from his own lab to illustrate the point. In 1 study, the team wondered whether they could convert the slow-growing, iron-oxidizing bacterium Mariprofundus ferrooxydans (a chemolithoautotroph) into one that uses sugars for metabolism (a heterotroph), like Escherichia coli. This would be experimentally useful, since, unlike E. coli, M. ferroxydans can only grow 1 way and generally produces low cell densities. Gralnick's lab inserted genes that allow for xylose and glucose utilization into M. ferroxydans's genome and assessed the bacterium's growth.
While the engineered bacteria did gain the ability to process sugars, they remained dependent on their native iron-based energy metabolism. For some reason, the bacteria couldn't let it go. "[This] kind of turned on [its] head what we thought would happen," Gralnick highlighted. "It tells us that we don't understand [the] metabolism sufficiently enough to be able to predict that."
This expansion of biological understanding is not separate from investigations of archaic life, but in service to them. A better idea of the metabolic dependencies and process of modern microbes provides more threads to pull on when researching their beginnings.
Advancing the Future by Exploring the Past
The moral of the story is that to understand life, we must dive into the past-and, if we are to understand the past, it helps to gain deep knowledge of life today. Synthetic biology can bridge that gap, with technological advancements continuously expanding what we can discover. A recent pre-print reported the development of a cell-like system that contains 36 enzymes, a 90,000 base pair genome and a lipid membrane. Known as SpudCell, the system can grow, replicate its genome and divide. It's the first time such a cell-like structure-built entirely from non-living components-has been generated.
"There's an incredible tool set available to us right now through synthetic biology," Kaçar said. "So, why not leverage that to understand early microbial life?"
Research in this article was presented at ASM Microbe 2026, the annual meeting of ASM, held June 4-7, 2026, in Washington, D.C. Session proposals for ASM Microbe 2027 are now open! Speakers play a critical role in shaping the scientific conversation at this annual meeting. We invite you to submit a proposal today!
For a deeper dive into early microbial life research, check out this American Academy of Microbiology report, funded by a grant from the Gordon and Betty Moore Foundation, examining the origins and trajectory of early microbial life to inform and inspire future investigations.
