How Enzymatic Synthesis is Powering the Next Biotech Era
For decades, the blueprint of life has been largely a read-only file. While we've mastered reading DNA through revolutionary sequencing technologies, writing DNA—the process of creating custom genetic sequences from scratch—has remained stuck in the past, reliant on 40-year-old chemical methods that are inefficient, limited, and environmentally damaging. Today, a seismic shift is underway as scientists pioneer a new approach inspired by nature itself: enzymatic DNA synthesis. This groundbreaking technology promises to transform industries from medicine to agriculture by making DNA writing as accessible as DNA reading, opening the floodgates to unprecedented innovation in synthetic biology and beyond 2 4 .
Since the 1980s, the synthetic DNA industry has relied almost exclusively on the phosphoramidite method, a chemical process that builds DNA strands using toxic organic solvents and corrosive reagents 1 5 .
Enzymatic DNA synthesis (EDS) represents a fundamental departure from traditional methods, drawing inspiration from how nature itself builds DNA 1 4 .
Enzymatic methods can directly produce DNA fragments up to 600 bases commercially, with early-access programs achieving 750-base oligos and assembled constructs up to 50 kilobases 1 5 .
EDS excels at producing sequences with challenging features like high GC content, repeats, and secondary structures that often stymie chemical synthesis 1 .
The race to commercialize enzymatic DNA synthesis features several innovative companies, each with distinct technological approaches and business models.
| Company | Core Technology | Key Products/Services | Distinguishing Features |
|---|---|---|---|
| Ansa Biotechnologies | TdT-dNTP conjugates | Commercial: 600 bp fragments, 7.5 kb clonal genes; Early access: 50 kb constructs 5 | Direct synthesis without assembly; exceptional handling of complex sequences 1 5 |
| DNA Script | TdT with protected nucleotides | SYNTAX benchtop printer (96 oligos/run); ssDNA oligo service (up to 500 nt) 1 | "Office printer" ease of use; focus on decentralization and rapid access 1 4 |
| Camena Bioscience | Proprietary enzymatic method | DNA synthesis for complex constructs | Partnering on synthetic chloroplast genome project 6 |
The commercial impact has been substantial. The gene synthesis market has exploded from $137 million in 2014 to over $2 billion by 2025, with the broader DNA synthesis market reaching approximately $6 billion and projected to grow to nearly $30 billion by 2035 2 . This growth is fueled by increasing demand from therapeutic development, synthetic biology, and agricultural biotechnology.
To understand why enzymatic synthesis represents such a leap forward, consider a key experiment conducted by DNA Script that demonstrates the technology's capability to assemble genes using long, enzymatically-synthesized oligonucleotides.
Using their enzymatic platform, researchers synthesized ssDNA oligos ranging from 200 to 500 nucleotides in length, including some designed with challenging features like high GC content and repetitive sequences .
For oligos longer than 300 nucleotides, researchers tested the effect of adding 5' adapter sequences (short, annealed DNA pieces) to improve integration efficiency during assembly .
The long ssDNA oligos were combined with other DNA fragments and subjected to Gibson Assembly, which uses a combination of exonuclease, polymerase, and ligase enzymes to join overlapping DNA pieces .
The researchers transformed the assembled DNA into bacteria, then screened individual clones to determine what percentage contained perfect assemblies, requiring minimal screening to obtain accurate constructs .
The experiment yielded impressive results that demonstrate the practical advantages of enzymatic synthesis for real-world applications.
| Oligo Length (nt) | Assembly Efficiency (% Perfect Clones) | Notes |
|---|---|---|
| Up to 300 | High (typically requiring screening of <5 clones) | No adapter needed |
| 400 | ~20% | With 5' adapter; need to screen ~4-7 clones |
| 500 | ~20% | With 5' adapter |
| Sequence Challenge | Example Construct | Result |
|---|---|---|
| High GC & Repeats | 299 bp with 78.9% GC content and GGGGGGGG repeat | Perfect assembly screening only ~4 clones |
| Tandem Repeats & G-Stretches | 420 bp fragment with complex repeats | ~20% perfect clones using adapter |
| Long Homopolymers | Poly(A) tails >300 nt | Routine synthesis, challenging for chemical methods |
This experiment demonstrates that enzymatic synthesis isn't merely a incremental improvement but a fundamental enabler for previously impossible genetic engineering projects. The ability to directly produce long, complex DNA fragments with high fidelity accelerates research timelines and expands the design space available to synthetic biologists.
The rise of enzymatic DNA synthesis has spawned a new generation of tools and reagents that are transforming laboratory capabilities.
| Tool/Reagent | Function | Application Examples |
|---|---|---|
| Engineered TdT Enzymes | Catalyzes template-free addition of nucleotides to growing DNA chain | Core engine of all enzymatic synthesis systems; various proprietary versions exist 1 4 |
| Modified Nucleotides | Building blocks with reversible terminator caps | Enable controlled single-base addition in DNA Script's approach 1 |
| TdT-dNTP Conjugates | Enzyme-nucleotide fusion molecules | Ansa's proprietary technology for precise single-base addition 1 5 |
| Specialized Solid Supports | Platform for water-based DNA synthesis | Compatible with aqueous enzymatic processes (unlike chemical synthesis supports) |
| Gibson Assembly Master Mix | Enzyme cocktail for seamless DNA assembly | Joining long EDS oligos into larger constructs |
Enzymatic synthesis offers a green alternative for writing digital information into DNA molecules, with potential for massive storage density and long-term stability 3 .
As enzymatic DNA synthesis continues to mature, its impact on biotechnology and society is expected to grow exponentially. The market projection speaks volumes: from approximately $6 billion in 2025 to nearly $30 billion by 2035, representing a compound annual growth rate exceeding 15% 2 . This growth will be fueled by continued technological advances and expanding applications.
Widespread adoption in research labs; early therapeutic applications; development of specialized enzymes and reagents.
Integration into clinical workflows; personalized medicine applications; industrial-scale biomanufacturing.
Routine synthesis of entire synthetic genomes; mainstream DNA data storage; transformative impact across multiple industries.
The transition to enzymatic methods represents more than just a technical improvement—it signifies a fundamental shift in our relationship with biology. As DNA writing becomes increasingly decentralized and accessible, we may see a revolution analogous to the personal computer's impact on computing. Just as personal computers democratized access to computing power and unleashed a wave of innovation, benchtop DNA synthesizers could democratize access to genetic engineering, empowering individual labs and even smaller institutions to pursue groundbreaking research 4 .
Ansa Biotechnologies, having secured $122 million in funding, now offers guaranteed on-time delivery—a previously unheard-of assurance in the DNA synthesis world 5 .
DNA Script has placed its SYNTAX systems in laboratories worldwide, bringing on-demand DNA printing directly to researchers 4 .
Collaborative projects like the effort to develop synthetic chloroplast genomes at the Max-Planck Institute illustrate how these technologies enable previously impossible scientific ambitions 6 .
The commercialization of enzymatic DNA synthesis represents more than just a technical upgrade—it marks a pivotal moment in biotechnology where our ability to write DNA finally matches our capacity to read it. By borrowing nature's tools and refining them for the laboratory, scientists have overcome the limitations of traditional chemical methods, opening new frontiers in medicine, manufacturing, and basic research. As this technology continues to evolve and democratize access to genetic engineering, it promises to accelerate our transition to a bio-based economy and unlock innovations we are only beginning to imagine. The DNA writing revolution has begun, and its impact will resonate for decades to come.