A New Paradigm: Programmable Biology Needs Programmable Manufacturing

Exploring How Programmable Manufacturing Can Solve the Challenges Posed by Modern Therapeutic Development

DNA Synthesis Moves From Lab Bench to Industrial Floor

Over the past two decades, biology has become increasingly programmable. Researchers can now design mRNA therapeutics with finely tuned regulatory elements, engineer patient-specific cell therapies, develop personalised cancer vaccines, and rapidly optimise antibodies using artificial intelligence and automation. The pace of therapeutic innovation has accelerated dramatically, but the way DNA is manufactured has evolved more slowly. Many of today’s manufacturing workflows were developed for an era of standardised medicines, where the objective was to produce the same construct repeatedly and at scale. The next generation of therapies has fundamentally different requirements. Instead of manufacturing one DNA sequence thousands of times, researchers increasingly need to manufacture thousands of unique DNA sequences, often in small quantities, often at short notice, and often as part of rapid design-build-test-learn cycles. The challenge is no longer simply designing better biology. It is creating manufacturing systems capable of producing increasingly complex DNA on demand.

Personalised therapies are changing what DNA needs to do

DNA has always been the foundation of therapeutic development, but the demands placed upon it are changing rapidly. Modern therapeutic platforms rely not only on coding sequences, but increasingly on sophisticated regulatory elements and complex genetic architectures that directly influence therapeutic performance. Consider mRNA therapeutics. While the protein-coding sequence is important, much of an mRNA molecule’s behaviour is determined by its regulatory elements. Optimised 5′ and 3′ untranslated regions (UTRs) help control translation efficiency and stability, while carefully designed polyA tails play a critical role in mRNA stability, protein expression and intracellular longevity. As our understanding of mRNA biology continues to evolve, developers are investing increasing effort in optimising these non-coding regions to improve therapeutic performance. However, these same features can introduce manufacturing challenges. Long regulatory regions, repetitive elements and extended polyA sequences may be more difficult to manufacture and maintain using conventional bacterial workflows, where polyA tails can progressively shorten during propagation. Similar challenges exist across other therapeutic modalities. Adeno-associated virus (AAV) vectors depend on inverted terminal repeats (ITRs), highly repetitive DNA sequences that are essential for packaging and function but are notoriously difficult to synthesise and maintain reliably. Cell and gene therapies frequently require larger and increasingly sophisticated DNA constructs, often incorporating multiple functional elements that must be assembled accurately while supporting rapid iteration throughout development. Meanwhile, antibody discovery programmes depend on highly diverse DNA libraries to explore enormous sequence space, placing increasing emphasis on manufacturing flexibility and speed rather than simply producing DNA at industrial scale. Taken together, these trends point towards a broader shift. Therapeutic development is becoming increasingly personalised, iterative and data-driven. DNA manufacturing must evolve accordingly.

Manufacturing was designed for a different era

Traditional DNA synthesis has enabled decades of scientific progress and remains an essential part of modern biotechnology. However, many existing manufacturing workflows were developed to support relatively standardised research and production models. Today’s therapeutic developers often face a different set of priorities. Rapid optimisation programmes demand turnaround times measured in days rather than weeks. Personalised medicines require smaller production volumes but many more unique constructs. Development teams increasingly modify designs based on experimental data, creating continuous cycles of redesign rather than single manufacturing campaigns. Living systems can also introduce biological constraints. Many conventional DNA manufacturing workflows rely on bacterial propagation following synthesis. While highly effective for many routine applications, host cells can struggle with particularly repetitive, unstable or otherwise challenging DNA sequences. Additional considerations, including endotoxin removal and sequence stability during propagation, can further complicate downstream workflows. These limitations do not diminish the importance of existing manufacturing approaches. Rather, they highlight that therapies are changing faster than the manufacturing infrastructure that supports them.

Cell-free enzymatic DNA synthesis changes what is possible

Supporting this new generation of therapeutics requires more than incremental improvements to existing workflows. It requires a different approach to DNA manufacturing. Cell-free enzymatic DNA synthesis (EDS) represents one such approach. Rather than relying on traditional phosphoramidite chemistry followed by propagation in living bacterial cells, EDS uses engineered enzymes to synthesise DNA under mild aqueous conditions within a completely cell-free environment. Removing the need for host-cell propagation changes what is possible. Without many of the biological constraints imposed by living systems, researchers gain greater flexibility when manufacturing complex, repetitive or otherwise challenging DNA sequences while reducing dependence on bacterial amplification. The practical benefits extend beyond the synthesis process itself. For mRNA developers, cell-free manufacturing can better support the production of templates containing long regulatory regions and precisely designed polyA tails. For gene therapy developers, it offers an alternative route for challenging vector components such as ITRs. For cell therapy and antibody engineering programmes, it supports the rapid iteration required as constructs become increasingly sophisticated and personalised. Most importantly, cell-free manufacturing aligns DNA production more closely with the pace of modern therapeutic development.

Programmable biology needs a new paradigm of manufacturing

The implications extend beyond how individual DNA molecules are produced. As biology itself becomes increasingly programmable, manufacturing must become equally flexible. Researchers increasingly expect to design a construct digitally, manufacture it rapidly, evaluate experimental results and immediately refine the next design. The process begins to resemble software development more than traditional manufacturing. This shift is driving renewed interest in integrated biological manufacturing environments capable of supporting on-demand DNA production. Biofoundries combine laboratory automation, robotics, software and advanced manufacturing technologies into highly integrated platforms that accelerate biological design-build-test-learn cycles. When combined with cell-free enzymatic DNA synthesis, these environments allow DNA manufacturing to move closer to the point of discovery, reducing delays between design and experimentation while supporting greater control over sensitive intellectual property. Equally important, biofoundries align manufacturing capacity with the emerging needs of personalised medicine. Rather than optimising for large production campaigns, they support flexible, on-demand manufacturing of precisely the DNA required, exactly when it is needed. This does not replace established manufacturing partners. Instead, it complements existing supply chains by providing researchers with additional flexibility for rapidly evolving programmes.

Building the infrastructure for the next generation of therapeutics

The future of therapeutic development will depend on far more than designing better medicines. It will depend on building manufacturing systems capable of keeping pace with increasingly programmable biology. Cell-free enzymatic DNA synthesis, on-demand manufacturing and integrated biofoundries represent more than advances in DNA production technology. Together, they are helping establish the biological infrastructure required for a future where therapies are increasingly personalised, rapidly iterated and continuously refined. As programmable biology moves from concept to reality, the ability to manufacture complex DNA on demand will become more than a competitive advantage. It will become a fundamental capability underpinning the next generation of therapeutic innovation.