How synthetic biology is transforming our understanding of genetic information flow through genome resynthesis, orthogonal biosystems, and synthetic genetics
Imagine if you could not only read a book but rewrite its chapters, change its language, and even add entirely new letters to its alphabet. For centuries, biologists studied life as it was written by nature, but a revolutionary shift is now underway: scientists are learning to rewrite the fundamental language of life itself. This transformation centers on expanding the Central Dogma of molecular biology—the once-rigid principle that genetic information flows exclusively from DNA to RNA to protein.
The original Central Dogma, formulated by Francis Crick in 1958, described a linear information flow that seemed as fundamental as Newton's laws of motion 8 . Just as physics evolved beyond Newton to embrace quantum theory, biology is now undergoing its own paradigm shift.
Today, synthetic biologists are not merely reading life's instruction manual but rewriting it through genome resynthesis, creating orthogonal biosystems that operate independently from natural biology, and developing synthetic genetics with entirely new molecular components 1 2 .
Designing and constructing entire genomes from scratch rather than merely editing existing ones.
Engineered to operate in parallel with natural biology without interacting with it.
The original Central Dogma compared living cells to simple computer programs: DNA contained the unchanging code, RNA served as the temporary messenger, and proteins executed the functions 8 . This model powerfully explained how genes determine traits in simple organisms, but it failed to capture the dynamic complexity of life's information systems.
The vast majority of human DNA (approximately 98%) doesn't code for proteins at all, contradicting the protein-centric view 2 .
A single gene can produce multiple different proteins through processes like alternative splicing, with the average human gene producing about six different proteins 8 .
Information flows bidirectionally—from environment to genome through epigenetic marks, and sometimes even from RNA back to DNA 3 .
Genome resynthesis involves designing and constructing entire genomes from scratch rather than merely editing existing ones. The landmark 2010 achievement by the J. Craig Venter Institute—creating the first bacterium with a fully synthetic genome—demonstrated that cellular life could be booted up from chemically synthesized DNA 1 7 .
More recently, the Sc2.0 project aims to resynthesize all 16 chromosomes of baker's yeast, introducing three revolutionary design principles:
Orthogonal biosystems are engineered to operate in parallel with natural biology but without interacting with it. These systems use different molecular components that function alongside a cell's natural machinery without cross-talk 1 6 .
The primary motivations for creating such systems include:
The most effective orthogonal systems combine multiple containment strategies, including semantic containment (changing the genetic code) and metabolic containment (dependence on synthetic nutrients) 1 .
Synthetic genetics represents perhaps the most radical expansion of the Central Dogma—adding entirely new letters to genetic alphabet and new words to the genetic code. Where nature uses only four nucleotide bases (A, T, C, G), synthetic biologists have created organisms with six and even eight-letter genetic systems 6 .
These expanded genetic systems enable:
These advances transform the Central Dogma from a fixed, universal principle into a malleable framework that can be extended, modified, and customized for specific applications.
One of the most ambitious experiments demonstrating the expanded Central Dogma is the creation of E. coli Syn61Δ3, a bacterial strain with a completely resynthesized genome using a compressed genetic code 1 . This project, completed in 2019, represents a landmark achievement in synthetic genomics.
The researchers employed a meticulous, multi-stage approach to reconstruct the E. coli genome:
Using sophisticated algorithms, the team identified all occurrences of three specific codons (TCG, TCA, and TAG) throughout the 4-million-base-pair genome and replaced them with synonymous alternatives (AGC, AGT, and TAA, respectively). This required 18,214 precise codon changes across the entire genome 1 5 .
The cellular components that recognized the removed codons—two serine tRNAs and release factor 1 (which recognizes stop codons)—were eliminated from the system.
The recoded genome was synthesized in large fragments (approximately 10-100 kb) using both in vitro methods (Gibson assembly) and in vivo assembly in yeast, which naturally performs homologous recombination 7 .
The synthetic genome fragments were systematically introduced into recipient cells, gradually replacing the native genome to avoid catastrophic disruptions to cellular function 7 .
The resulting Syn61Δ3 strain successfully grew and reproduced, demonstrating that fundamental cellular processes could be maintained despite the dramatic genetic overhaul. However, the researchers observed several fascinating phenotypic consequences:
| Parameter | Wild Type E. coli | Syn61Δ3 | Significance |
|---|---|---|---|
| Genetic Code Size | 64 codons | 61 codons | First organism with a compressed genetic code |
| Genome Size | ~4.6 Mbp | ~4.0 Mbp | 18,214 codons rewritten |
| Growth Rate | Normal | ~1.6x slower | Recoding affects cellular processes |
| Cell Length | Normal | ~1.5x longer | Morphological changes from genetic compression |
| Genetic Isolation | None | Resistant to viral infection | Semantic containment demonstrated |
The most significant finding was that Syn61Δ3 exhibited strong genetic isolation from natural organisms. Bacteriophages that successfully infected wild-type E. coli could no longer infect the recoded strain, as their genetic messages became incomprehensible to the synthetic organism 1 . This demonstrated the concept of semantic containment—using genetic code differences as a powerful biosafety tool.
| Freed Codon | Original Function | Potential Applications |
|---|---|---|
| TCG | Serine encoding | Unnatural amino acid incorporation |
| TCA | Serine encoding | Chemical synthesis of novel polymers |
| TAG | Stop signal | Orthogonal code for synthetic biology |
The expansion of the Central Dogma relies on a sophisticated toolkit of synthetic and engineered biological components. These research reagents enable the creation of organisms with altered genetic codes and orthogonal biological systems.
Engineered ribosomes that translate only orthogonal mRNAs, enabling parallel protein synthesis systems 1 .
Enzyme-tRNA pairs that don't cross-react with natural systems, allowing unnatural amino acid incorporation 1 .
Xenonucleic acids - alternative genetic polymers with novel properties for developing new biological functions 1 .
RNA-guided DNA targeting and manipulation tools for genome editing, regulation, and imaging 3 .
Inducible chromosome recombination system for accelerated evolution and genome rearrangement 7 .
These tools collectively enable what might be termed "biological orthogonality"—the ability to create parallel biological systems within the same cell or organism that function independently from natural systems 6 . This represents perhaps the most profound expansion of the Central Dogma, transforming biology from a singular, universal system into a potentially pluralistic one where multiple genetic codes and molecular languages can coexist.
The expansion of the Central Dogma from a rigid, unidirectional flow to a dynamic, customizable information network represents a fundamental transformation in how we understand and interact with living systems. Through genome resynthesis, creation of orthogonal biosystems, and development of synthetic genetics, biology is evolving from a descriptive science to an engineering discipline.
Organisms with rewritten genetic codes could produce medicines using amino acids not found in nature.
Orthogonal biosystems might serve as computational systems that perform calculations in parallel with natural cellular functions.
Semantic containment strategies could ensure that synthetic organisms remain genetically isolated from natural ecosystems.
Perhaps most profoundly, these developments challenge us to reconsider fundamental questions about life's nature. If organisms can be created with different molecular components and genetic codes from natural life, what truly defines "life" at its most essential? The expanded Central Dogma suggests that life may be less about specific molecules and more about information patterns that can be instantiated in multiple chemical forms.
As we continue to push the boundaries of biological design, we're not merely discovering life's rules—we're learning to write new ones. The expanded Central Dogma represents both a scientific revolution and a philosophical one, reminding us that in biology, as in all sciences, today's dogmas often become tomorrow's expanding horizons.