Writing for Nature in March 2023, Carrie Arnold explores the possibilities presented by cell-free processes. Arnold identifies a “growing number of biomanufacturing firms” that are “embracing” a cell-free biosynthesis strategy.  

Without relying on yeast or bacteria for biomolecules, researchers have been able to remove the “components of a cell that make it ‘alive’”, including DNA and endoplasmic reticulum. By freeze-drying “what remains”, scientists are able to rehydrate this material and programme the “molecular machinery” with nucleic acids. The result? An “infinite array of proteins on demand”.  

Baking a biological cake or exploiting a car engine 

Professor Tobias Erb of the Max Planck Institute for Terrestrial Microbiology in Germany suggests to Arnold that the process is like using a cake mix to which the baker simply adds water. This allows biology to “become more chemically diverse” whilst allowing “chemistry to become more complex”, he says.  

For Professor Michael Jewett of Northwestern University in the US, it is similar to opening up a car bonnet to extract the engine and repurpose it to power a drill. Professor Jewett has demonstrated that ribosomes in cell-free systems can be “used to build biopolymers with new chemical backbones, as well as proteins”.  

From research to manufacturing 

Arnold states that cell-free systems have been used for biochemical reactions “for decades”, but largely in research settings. 

“Now, thanks to advances in both reliability and scale, cell-free synthesis is emerging as a major tool for everything from diagnostic-sensor development to vaccine biomanufacturing.”  

Despite these advances, there are “hurdles” to overcome, such as the complication of “key protein modifications”. This will be a matter of engineering, says Professor Matthew DeLisa of Cornell University.  

“Cell-free systems turn protein synthesis into more of a chemistry problem than a biology problem.” 

However, biomanufacturing has been “slow to adopt the technology”, Arnold suggests, partly due to “inertia”. Professor James Swartz of Stanford University thinks it has “taken a long time for people to wrap their heads around the idea”.  

“We don’t need a living organism to do complex metabolism, to make complex molecular rearrangements, even to make complex proteins”.   

Arnold also believes that the transition has been slow due to the low cost and ease of growing large quantities of bacteria and yeast in comparison with running biochemical reactions. These “require expensive reagents” and “energy sources” as well as other materials. Furthermore, cells “can generate higher yields of the desired product”. 

However, we are now seeing the fruits of “years of molecular tinkering” to improve cell-free systems.  

Storing cell-free 

Professor Jewett identifies key element to the attraction of cell-free processes. As we know, refrigeration and complex cold chain requirements for vaccine products put pressure on both development and distribution. For cell-free preparations, however, researchers can store products for longer periods and rehydrate on demand.  

“It’s kind of like freeze-dried ice cream – something you can transport wherever you go.”

The pressure that storage and distribution place on vaccine deployment was highlighted during the COVID-19 pandemic, says Dr Jessica Stark of Stanford. 

“We need better ways to make and distribute medicines very quickly in order to address emerging pathogens.”  

What will we do with cell-free systems? 

Arnold identifies an “expanded repertoire of applications” for these cell-free processes. So, too, does the US Army, which has awarded $13 million to a new Cell-Free Biomanufacturing Institute at Northwestern University.  

However, cell-free systems “remain enormously complex” and we don’t have a “good enough handle” on the process and the potential for scaling up.  

“But as cell-free systems take their place in the biomanufacturing toolset, they are providing researchers with a new and increasingly attractive option: just add water.”  

For more on innovation in the vaccine development space, join us at the World Vaccine Congress in Washington this April.