genome recoding for synthetic proteins

Scientists Recode the Genome to Create Programmable Synthetic Proteins

Breathrough in Genome Recoding

Yale synthetic biologists have successfully reprogrammed an organism's genetic code, creating a novel genomically recoded organism (GRO) with a single stop codon. Using a specially developed cellular platform, they have enabled the production of entirely new classes of synthetic proteins, which hold vast potential for advancing medical and industrial applications.

A Revolutionary Genomically Recoded Organism: 'Ochre'

What is 'Ochre'?

A groundbreaking genomically recoded organism (GRO), named 'Ochre,' has been developed by compressing redundant or 'degenerate' codons into a single codon. This achievement is detailed in a newly published study in Nature. Codons, sequences of three nucleotides in DNA or RNA, encode specific amino acids, the fundamental components of proteins.

Engineering Genetic Systems for Biotherapeutics and Biomaterials

"This study provides insights into the plasticity of genetic codes," said Farren Isaacs, professor of molecular, cellular, and developmental biology at Yale and co-senior author. "It also showcases our ability to engineer genetic systems to create multifunctional proteins, ushering in a transformative era for biotherapeutics and biomaterials."

Building on the 2013 GRO Study

This groundbreaking advancement builds upon the team's 2013 Science publication, which detailed the creations of the first genomically recoded organism (GRO). That study introduced novel strategies for enhancing the safety of genetically engineered organisms while enabling the production of synthetic proteins and biomaterials with artificial, human-designed chemistries.

Advancing Non-Redundant Genetic Code in E. coli

Ochre represents a significant advancement toward establishing a streamlined, non-redundant genetic code in E. coli, an organism well-suited for synthesizing proteins that incorporate multiple distinct synthetic amino acids.

Engineering the Genome - A New Scale of Innovation

Jesse Rinehart, associate professor at Yale School of Medicine and co-senior author, described the research as a groundbreaking demonstration of whole-genome engineering, achieving over 1,000 targeted edits-an innovation that significantly surpasses all previous genetic engineering milestones.

Unlocking Applications in Research and Industry

"This groundbreaking platform technology paves the way for a wide range of biotechnological applications across both academic research and commercial industries," said Rinehart. "Our goal is not only to expand scientific knowledge but also to drive industrial innovations that benefit society."

Understanding Codons and Their Role in Protein Engineering

What are Codons?

The codon, a three-nucleotide sequence found in DNA and RNA, functions as a genetic blueprint for protein synthesis. It instructs the cell on which of the 20 natural amino acids to integrate into a developing protein chain or, if a 'stop' codon is encountered, to cease synthesis. This process, known as translation, enables mRNA to regulate both the sequence of amino acids and the initiation and termination of protein formation.

Redefining the Genetic Code

Michael Grome, a postdoctoral associate in molecular, cellular, and developmental biology at Yale and first author of the study, compare codons to three-letter words in the genetic blueprint of life. He explained that within the cell, ribosomes function like 3D printers, interpreting this genetic code. Each codon specifies a single amino acid, selected from the 20 natural amino acids that form proteins.

Removing Redundancy to Expand Functionality

"Many of these codons are synonymous, meaning they convey the same instruction," explained Grome. "Our goal to expand the set of available building blocks for proteins. To achieve this, we consolidated three stop codons into one, effectively removing two and reprogramming the cell to repurpose them for new functions. We then engineered the cell to interpret these freed codons as instructions for incorporating novel amino acids."

AI-Guided Engineering for Synthetic Biology

The researchers strategically removed two to the three stop codons responsible for terminating protein synthesis. In the recoded genome, four codons were reassigned to novel, non-redundant roles, including the two modified stop codons, which were repurposed to encode nonstandard, or synthetic, amino acids within proteins.

Beyond implementing thousands of precise genomic edits, the study leveraged AI-driven desing and the re-engineering of key protein and RNA translation factors to develop a strain capable of incorporating two nonstandard amino acids into its genetic framework.

Expanding Functional Capabilities of Proteins

The incorporation of these nonstandard amino acids grants proteins novel functionalities, enabling the development of programmable biologics with reduced immunogenicity and biomaterials with enhanced elecrical conductivity.

A Decade-Long Collaboration in Genome Engineering

These findings represent the culmination of years of genome recoding research conducted by two laboratories at the Yale Systems Biology Institute on West Campus.

Complementary Expertise in Genome and Protein Engineering

The collaboration between Rinehart and Isaacs began in 2010 when they worked in adjacent labs. Isaacs, likening his work to architectural planning, has focused on genome engineering, while Rinehart's research centers on protein synthesis and their functional potential.

"We realized that our skill sets were complementary and that both labs contribute a diverse range of expertise and technical capabilities,' Rinehart stated.

Future Applications of Programmable Protein Biologics

Isaacs is enthusiastic about what he considers game-changing applications for programmable protein biologics enabled by this new platform.

One promising avenue involves designing protein-based therapeutics with synthetic chemistries to reduce dosing frequency and mitigate adverse immune responses.

Validating the Approach - The 2022 Study

The team previously demonstrated such an application in a 2022 study utilizing their first-generation GRO.

By incorporating non-standard amino acids into proteins, they introduced a safer and tunable approach to modulating the half-life of protein biologics.

Bringing Programmable Biologics to Market

The Ochre cell enhances these capabilities, enabling the development of multifunctional biologics. Isaacs and Rinehart currently serve as advisors to Pearl Bio, a Yale biotechnology spin-off that has secured licensing rights to commercialize programmable biologics.

Source

"Unlock the Future of Genetic Engineering!

Yale scientists have achieved a groundbreaking milestone in synthetic biology by recoding the genome to create programmable synthetic proteins. This revolutionary advancement paves the way for next-generation biopharmaceuticals, enhanced biomaterials, and novel protein-based therapeutics.

How will this impact medicine, biotech, and industrial applications?

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