Synthetic biology is ready for the therapeutic limelight

Mandell, Dan

Article

Synthetic biology is ready for the therapeutic limelight

22 September 2022

After initially serving as a proving ground for integrating forward engineering principles into living cells, synthetic biology is making waves across diverse therapeutic areas. In this article, Dr Dan Mandell, Co-Founder and CEO of GRO Biosciences, explains how the field is reshaping our understanding of the limits of cell- and molecular-based medicines.

As synthetic biology passes 20 years as an established discipline, the field is poised to deliver ground-breaking therapies and cures for diseases currently out of reach to traditional therapeutic modalities. The field emerged in the early 2000s from a coalescence of readily available molecular biology tools and a desire to bring predictable, programmable-like robustness to cell engineering. Early successes demonstrated proof-of-concept for reusable molecular parts and tunable genetic circuitry. However, cellular systems are inherently noisy and non‑digital; the resistance of cells to comply with traditional principles from electrical and computer engineering therefore hampered the applicability of synthetic biology tools to real-world problems. Consequently, the field was critiqued for the fragility and context-dependence of its early engineered parts and circuits.¹

Multiple significant developments in biotechnology, however, have now positioned synthetic biology as a powerful force in tackling society’s biggest challenges – including those in the clinic. These advances include a thousand-fold reduction in the cost of DNA synthesis, improvements to molecular design software, parallelised computational infrastructure and the integration of high-throughput robotics into laboratories capable of screening orders-of-magnitude larger libraries of cell- and molecular-based therapies. Furthermore, these are all supported by an attendant increase in our understanding of cellular and physiological behaviour in normal and disease phenotypes. Therapeutic applications of these next-generation synthetic biology systems can be broadly divided into two groups: cell‑based and molecular-based medicines.

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The three key challenges to providing safe and effective cell therapies are delivering the therapy to the intended tissue, tuning the timing and dose response of the therapeutic action and preventing adverse reactions from the patient’s immune system.² Synthetic biology has developed innovative and unique solutions to all three problems. Genetic implementations of Boolean logic such as AND gates enable engineered cells to home to and activate in the presence of cells bearing defined surface markers. T cells have been engineered to target and kill melanoma cells without affecting neighbouring cells by recognising multiple distinct tumour antigens.^3,4 Synthetic “kill switches”⁵ and “ON switches”⁶ enable spatiotemporal control of cell therapies through activation or deactivation by defined signals, such as small molecules or light.

Meanwhile, protein-based signal transduction offers much faster transmission of information than genetic circuits due to the latter’s dependence on RNA transcription and protein translation. Recent advances in computational protein design allow for changes in protein conformation to encode similar Boolean logic as genetic circuits. Such approaches have been used to design protein complexes that target cells overexpressing two tumour antigens but lacking a third marker.⁷ Biotechnology companies like Outpace are using related technologies to improve targeting and reduce side effects for cell‑based cancer therapies.

Synthetic biologists have further developed microbial cells functioning as in situ therapeutic factories, secreting therapeutic molecules in defined physiological niches. These ‘living medicines’ have shown promise in human and animal studies of Crohn’s disease⁸ and diabetes.⁹ Companies like Synlogic have clinical trials underway assessing living medicines for the treatment of phenylketonuria, homocystinuria and enteric hyperoxaluria. For such cell therapies to achieve clinical relevance, it is critical that they avoid unwanted immune reactions. To this end, synthetic biologists have performed genome-wide screens using the gene editing tool CRISPR to find gene deletions that enable engineered cells to escape immunosuppression.¹⁰

In parallel to cell-based advances, synthetic biology has brought further capabilities to molecular-based medicines, which include small molecule, nucleotide and protein therapeutics. Researchers have combined computational data mining tools from systems biology with synthetic biology methods to engineer biosynthetic gene clusters (BGCs). These BGCs reconstitute and reengineer natural gene clusters from heterologous sources in more common microbial production chassis for increasingly efficient production of molecular therapeutics. Fine tuning of BCGs has enabled biosynthetic production of the antimalarial artemisinin¹¹ and various opioids.¹² Warp Drive Bio, acquired by Revolution Medicines in 2018, developed BGCs from genome mining that produce novel antibiotic and cancer therapy candidates.

Perhaps the greatest promise of synthetic biology for molecular medicine is to expand the universe of capabilities beyond those explored by nature. At a fundamental level, this expansion entails access to molecular building blocks with chemistries that are naturally unavailable. Variously termed non-canonical amino acids, unnatural amino acids, non-proteinogenic amino acids and non-standard amino acids (NSAAs), these alternative protein building blocks first became accessible to peptide therapeutics through advances in solid-phase peptide synthesis (SPPS). Thousands of NSAAs have been synthesised¹³ and many have endowed therapeutics with previously unattainable properties. The NSAA aminoisobutyrate provides the GLP-1 agonist semaglutide (Ozempic) with protease resistance essential to achieving its once-weekly dosing cadence. The NSAAs citrulline and L-3-benzothienylalanine have been used to increase the potency of HIV protease inhibitors.^14,15 Two other NSAAs, methylphenylalanine and cyclohexylalanine, increase the ability of peptide therapeutics to cross the blood-brain barrier.¹⁶ NSAAs with D enantiomers have been used to decrease peptide immunogenicity,¹⁷ while others like p-nitrophenylalanine have been incorporated to elicit a stronger targeted immune response against tumour cells.¹⁸

While enhancing peptides with NSAAs has produced blockbuster medicines, the majority of biologics are proteins that are too large for SPPS. Accessing the full power of protein diversity currently requires cell-based ribosomal translation. NSAAs can be incorporated into proteins through ribosomal translation by introducing a transfer RNA (tRNA) and aminoacyl-tRNA synthetase (aaRS) pair that operate orthogonally to other machinery in the production cell. An engineered aaRS can attach an NSAA of interest to a tRNA with specificity to a target codon, enabling site-specific NSAA incorporation in a protein coding sequence. As all codons are utilised in an organism’s genetic code, in vivo translation of NSAA proteins is typically limited by off-target incorporation of NSAAs into undesired sites in the genome (impairing organismal fitness) and by competition with endogenous translation machinery evolved to recognise the same codon (impairing NSAA protein production). Cell-free protein expression offers a route to avoiding competition between host and NSAA translational machinery. Working with purified components derived from both natural and engineered sources, researchers can selectively remove cell machinery that would compete with NSAA tRNA for recognition of target codons. Sutro Biopharma has developed cell-free production systems for incorporating NSAAs for specific conjugation chemistries and has brought multiple NSAA-enabled antibody-drug conjugate (ADC) cancer therapies into clinical trials.

Achieving commercial scale with tractable economics for most NSAA protein therapeutics will likely require exploiting the exponential growth and productivity afforded by in vivo production systems. Ambrx pioneered in vivo production of NSAA therapeutics using tRNA suppression, which attempts to produce sufficient intracellular NSAA‑tRNA to withstand competition from endogenous tRNAs for target codons. The company has brought an NSAA-enabled oncology ADC into Phase III clinical trials in partnership with the Chinese biopharma organisation Novocodex. Challenges with scalability arising from the above-described off-target incorporation and translational competition may limit broader adoption of the technology. Synthorx (acquired by Sanofi in 2020) addressed the challenge of competition through the addition of an unnatural nucleotide pair that can encode hundreds of new codons.¹⁹ Synthorx and Sanofi developed a not‑alpha IL-2 immuno-oncology therapy by conjugating a PEG molecule to IL-2 via an NSAA that blocks association with IL‑2Ralpha, currently in Phase I clinical trials. While expansion of accessible codons in Synthorx’s production system addresses inefficiencies arising from translational competition, additional challenges to scalability may arise from the energetically costly measures necessary to maintain the unnatural nucleotides and associated transport machinery.²⁰

Figure 1: GROs enable scalable production of NSAA protein therapeutics.1 GROs are cellular production factories with modified genomes and engineered protein translational machinery.2 In a GRO, target codons are present only in the gene of interest, maintaining high organismal fitness and productivity.3 Protein translation machinery that recognises the target codon is deleted in a GRO (in this case, a Release Factor that would terminate translation at the target codon is deleted), removing competition for NSAA incorporation into the protein product.4 A standard production organism will produce truncated or inactive NSAA proteins, while GROs enable high-efficiency production of full-length, active NSAA proteins at commercial scale.

To enable scalable NSAA therapeutic production in systems that are also evolutionarily stable, GRO Biosciences is commercialising its genomically recoded organism (GRO) platform (Figure 1). Two key changes from standard production organisms facilitate scalable NSAA protein production in GROs. First, all instances of a target codon in the organism’s genome are converted to a synonymous codon via gene editing²¹ or whole genome synthesis.^22,23 These changes eliminate off-target incorporation of NSAAs into the GRO genome without altering or impairing host gene functions. Second, with no instances of the target codon remaining in the genome, translational machinery recognising the target codon is deleted, removing any competition with NSAA translational machinery. Now NSAAs can be installed with high fidelity at any position in a therapeutic protein by placing the target codon in the protein’s coding sequence, which may be contained in an expression plasmid or on the GRO’s genome. As reversion to the wild-type genotype requires hundreds to thousands of changes to occur simultaneously, GROs are evolutionarily stable production organisms and have been successfully fermented.

Figure 2: DuraLogic NSAAs enable persistent therapeutic activity in destabilising in vivo environments. DuraLogic therapeutics resist degradation by proteases, aggregation and chemical reduction, endowing them with flatter pharmacodynamic profiles for reduced side effects and prolonged duration of action for more convenient administration.

With access to a limitless set of NSAA chemistries, GRO Biosciences has developed a pipeline of pre-clinical-stage NSAA proteins that open new therapeutic modalities. The company’s DuraLogic™ NSAAs endow proteins with stability against chemicals encountered in in vivo environments like proteases and reducing agents (Figure 2). DuraLogic NSAAs provide flatter pharmacodynamics for reduced side effects and longer duration of action for more convenient dosing. Separately, the company’s ProGly™ NSAAs are glycosylated amino acids that afford precise control of the immune response to a protein (Figure 3). By decorating an immunogenic protein with tolerising glycans, ProGly therapeutics can reverse an autoimmune response to an antigen or eliminate neutralising antibodies that currently impair the efficacy and safety of enzyme replacement therapies and gene therapy vectors.

Figure 3: ProGly NSAAs enable precise control over immunogenicity. ProGly NSAAs can re-educate the immune system to treat autoimmune disease or to eliminate anti-drug antibodies against other-wise promising therapeutics. In the standard pathway (upper panel), the immune system recognises an antigen as a foreign protein and mounts an immune response. In the ProGly pathway (lower panel), ProGly NSAAs bear glycans that signal to the immune system that the antigen is a self-protein, reversing the immune response.

Efficient production of NSAA therapeutics in GROs faces challenges. The process of genomic recoding – swapping all instances of target codons to synonymous codons – can introduce off-target changes to the genome that require discovery, characterisation and reversion.²⁴

Furthermore, while a synonymous codon substitution yields equivalent function at the protein level, such changes may disrupt cryptic functions inherent to the underlying mRNA sequence, such as promoters, overlapping genes or mRNA secondary structure. The company has codified learnings from recoding efforts into genome design rules to mitigate such disruptions.^25,26 As a further challenge, adding an NSAA to the platform requires engineering orthogonal aaRS and tRNA pairs – a process that has typically been slow, expensive and hampered by poor specificity. The company has built a biofoundry that combines computational protein design tools with high-throughput robotics to bring order‑of-magnitude improvements to the speed and specificity achieved in engineering NSAA translational machinery. Finally, synthesising NSAAs can be costly. While economies of scale are expected to depress long-term costs, biosynthesis of NSAAs can bring immediate gains. For example, one of GRO Bioscience’s DuraLogic NSAAs is selenocysteine, which is synthesised within the GRO from an organic selenium salt that adds only $0.004/L to the cost of cell culture.

Synthetic biology has advanced from proving engineering concepts for predictable cellular behaviours to opening the doors to cell- and molecular‑based therapeutic modalities that were previously impossible. In the coming years we can expect to see allogenic cell therapies that are highly specific and immunosilent, together with engineered autologous cell therapies that do not require immunosuppression. Living medicines will integrate multiple physiological indicators to deliver therapeutics in situ on an as-needed basis. The field will move from single organisms to engineered consortia that carry out complementary functions in defined environments that would be impossible for a single compartmentalised organism. The expansion of molecular building blocks like NSAAs and unnatural nucleotides will support and encourage the development of therapeutics with cutting-edge capabilities such as chemical- and light-based control of activity, intracellular drug delivery and precise immunoregulation.

About the author

Dr Dan Mandell is Co-Founder and CEO of GRO Biosciences. He is a leading expert in synthetic biology, protein engineering, artificial intelligence and biological and medical informatics. Together with Dr George Church, he leveraged genomically-recoded organisms to produce the first proteins with stability and function dependent on non-standard amino acids. Dan completed his research fellowship in genetics at Harvard Medical School. He completed his PhD at the University of California, San Francisco, his MSc at University of Edinburgh and his undergraduate degree in Symbolic Systems from Stanford University.

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