New Engineered Ribosome Makes Just One Protein

Every cell depends on ribosomes, the molecular machines that translate genetic instructions into proteins. Because a cell needs thousands of different proteins on hand at once, ribosomes typically act as generalists, able to build almost any protein from any set of instructions.

A team at the University of Illinois Chicago has engineered a different kind of ribosome: one built to produce only a single protein. The work, published in Nature, presents a new platform for synthetic biology that remains in an early stage of development but that the authors say could someday be applied to designer peptide-based drugs.

Called Ribo-M, the platform physically links a ribosome to messenger RNA, the genetic instructions for making a specific protein. Study author Kasra Alizadeh described the limitation of ordinary ribosomes: “Natural ribosomes need to look around the cell to find the blueprint or the recipe for any of the hundreds of proteins to synthesize.” That works well for normal cell function, but can limit biotechnology efforts that call for cells to produce unusual proteins, therapeutic molecules, or other engineered products. 

The researchers addressed this by building the genetic instructions directly into the ribosome. “We decided to overcome this problem by incorporating the message into the ribosome itself,” said corresponding author Alexander Mankin. “Our engineered ribosomes are specialized,” Alizadeh said. “They always carry with them the recipe for one specific protein and only focus on making that protein without having to waste time looking around.”

Reaching a working design took years of trial and error: the team generated tens of thousands of ribosome variants and screened thousands of bacterial colonies before finding one that functioned. The researchers then showed that Ribo-M could produce several different proteins, including one that creates green fluorescence, an antibiotic-resistance protein, and a light-producing enzyme.

That specialization could eventually let ribosomes be tuned to build proteins with properties not found in nature, including ones that incorporate nonstandard amino acids. “We can teach the ribosome to incorporate non-canonical amino acids into a protein,” Mankin said. “One day, such a ribosome will be able, for example, to make therapeutic antibodies that survive longer in the body.”

Still, Mankin was clear about where the technology stands now: “This is a prototype. This is not even the Wright brothers’ airplane. This is the bicycle with wings.”

The team points to a longer-term path toward peptide-based medicines, such as semaglutide, the active ingredient in drugs like Ozempic, which is currently made through complex manufacturing processes. Specialized ribosomes, they say, could someday help cells produce such molecules more efficiently. “This is just the beginning of a long list of opportunities that our invention can unlock,” Alizadeh said. “These specialized ribosomes can serve as an exclusive protein synthesis platform, which can be fine-tuned by synthetic biologists for the production of designer drugs, enzymes and other proteins.”

The design may also offer a model for how the earliest protein-making systems could have worked, since it combines protein-making machinery and genetic instructions into a single unit, resembling conditions that may have existed before cells held large numbers of free-floating ribosomes and messenger RNAs.