What sets the work apart is that the metabolic pathway does not exist in nature.Getty Images
Turning climate pollution into something useful has long been a scientific ambition.
Now, researchers in the U.S. have taken a bold step toward that goal by building an entirely artificial metabolism that can convert carbon dioxide–derived molecules into valuable chemical building blocks.
Synthetic biologists from Northwestern University and Stanford University have engineered a new system that transforms formate, a simple liquid molecule easily produced from captured CO₂, into acetyl-CoA, a central metabolite used by all living cells.
As a proof of concept, the same system was then used to convert acetyl-CoA into malate, a commercially valuable compound used in food products, cosmetics, and biodegradable plastics.
What sets the work apart is that the metabolic pathway does not exist in nature.
Instead of relying on living organisms, the researchers built a fully synthetic, cell-free system composed of engineered enzymes capable of carrying out reactions never previously observed in biology.
The system, known as the Reductive Formate Pathway, or ReForm, represents a major advance in synthetic biology and carbon recycling, with potential implications for carbon-neutral fuels and sustainable manufacturing.
Metabolism beyond living cells
Unlike natural metabolic routes that operate inside organisms, ReForm functions entirely outside living cells.
This design allows researchers to bypass biological limitations that have long hindered efficient CO₂ utilization.
“The unabated release of CO2 has caused many pressing social and economic challenges for humanity,” said Northwestern’s Ashty Karim, who co-led the study.
“If we’re going to address this global challenge, we critically need new routes to carbon-negative manufacturing of goods.”
Karim explained that while nature has evolved pathways to process CO₂, none can convert formate into acetyl-CoA.
“Inspired by nature, we sought to use biological enzymes to convert formate derived from CO2 into more valuable materials,” he said. “Because there isn’t a set of enzymes in nature that can do that, we decided to engineer one.”
The ability to work outside cells also gives scientists precise control over enzyme concentrations, reaction conditions, and cofactors, something that is nearly impossible to achieve inside living systems.
Engineering enzymes at speed
To make ReForm work, the team first had to create enzymes capable of performing entirely new chemical tasks.
They turned to cell-free synthetic biology, a technique that extracts a cell’s molecular machinery and operates it in a test-tube environment.
“It’s like opening the hood of a car and removing the engine,” said Stanford’s Michael Jewett, who co-led the study. “Then, we can use that ‘engine’ for different purposes, free from the constraints of the car.”
This approach allowed the researchers to rapidly screen 66 enzymes and more than 3,000 enzyme variants, identifying the best performers in weeks rather than months.
“The cell-free environment enabled us to test thousands per week,” Karim said.
In the final design, five engineered enzymes carry out six reaction steps to convert formate into acetyl-CoA. The team also showed that ReForm can accept other one-carbon inputs, including formaldehyde and methanol.
“ReForm can readily use diverse carbon sources,” Jewett said. “This is the first demonstration of a synthetic metabolic pathway architecture that can do so.”
The researchers say the platform could be further optimized and adapted to build other synthetic pathways that blend chemistry and biology, offering new tools for carbon-efficient manufacturing, as detailed in Nature Chemical Engineering.
