Using Synthetic Biology to Create Therapeutic Solutions

THE SYNTHETIC biology industry is in a heyday of medical and pharmaceutical innovation, bringing new hope for chronic diseases. The ability to create living cells from nonliving components, to reprogram cellular functions and design new biological pathways, to create therapeutic interventions that may one day mitigate complex immune diseases and metabolic disorders, provide cures for cancers and infectious diseases and positively affect a myriad of health disorders is an exciting field of study. Synthetic biology is also changing approaches to personalized drugs and drug delivery systems. Together, this rapidly expanding industry is expected to reach $37 billion by 2026¹ and by some estimates $100 billion by 2030.²

The field of synthetic biology began growing rapidly in the 1990s when ex vivo genetically corrected lymphocytes were used to treat two patients with severe combined immunodeficiency caused by adenosine deaminase deficiency. Since then, next-generation DNA sequencing and progress in engineering biology have birthed overlapping fields of research that will one day enable treating, replacing and repairing malfunctioning cells and genes for the benefit of diseases difficult to treat by traditional means.³

In fact, synthetic biology is at the crossroads of biology, engineering and artificial intelligence (AI). Faster and more sophisticated data analysis and predicted effects may one day limit the need for lengthy laboratory tests to gain approvals from the United States Food and Drug Administration, as was seen with the design and emergency use authorization of the COVID-19 vaccines.

At its core, one of the many challenges of synthetic biology is creating an artificial cell that bypasses protein synthesis as it transcripts/translates genetic information. But, as researchers combine, reengineer and equip organisms to create artificial biological smart cell networks, the benefits could be endless.

Today, synthetic immune cells already have the ability to sense, detect and treat some diseases the natural immune system has difficulty coping with, sending engineered proteins to their target cells and triggering desired changes in gene expression. For instance, engineered human kidney cells are showing promise for maintaining glucose homeostasis and correcting diabetic hyperglycemia in mice; they are also changing fibroblasts into cells similar to stem cells that can be used therapeutically, all without using human embryos.1 New innovations and uses for synthetic biology continue to be uncovered, each moving one step closer to targeting diseased cells without impacting healthy cells.

But, synthetic biology is not without controversy, including the ethical questions of genetic engineering, equity and access. Still, the power of this incredible field of study is promising to bring the reality of comprehensive personalized medicine one step closer.

Synthetic Immunity

The immune system is a delicate balance, with cells continuously detecting and responding to disease and imbalances. Sometimes that response is targeted, such as killing invader cells, and sometimes the response is more subtle, such as with the secretion of cytokines and chemokines that recruit cells to target the problem. But, with the advent of synthetic biology, immune cells can be removed, modified, reprogrammed and reinserted into the patient when their natural immunity cannot cope with existing threats. This approach creates a new, long-term protective memory against the disease, thereby reducing the risk of relapse.⁴

The idea of improving one’s immune system via the introduction of synthetic cells is an innovative approach, one that some believe has advantages over traditional cellular therapies because of synthetic’s ability to be designed with molecular-level precision and focus on singular targets in a way that mirrors and integrates with one’s systemic natural immunity⁵ with a lower risk of harming healthy cells.

In controlling things like T-cell activation and elimination of bacteria, desirable phenotypes may be brought online more effectively.⁵ Today, modification of the patient’s own cells is most common, though in the future, creating engineered nonhuman cells may be a more cost effective, normal practice.

Metabolic Diseases

Metabolic diseases are often chronic and genetically influenced, and frequently involve complex metabolic imbalances. Traditionally, therapies used to treat metabolic diseases manage symptoms rather than cure the underlying cause. However, synthetic biology enables the development of tailored solutions such as reprogramming cellular functions and creating new biological pathways that can address these disorders at their roots.

For example, engineered bacteria offers an opportunity to positively influence a number of metabolic diseases. In laboratory mice on a high-fat diet, engineered gut bacteria are successfully delivering the incretin hormone GLP-1 to stimulate B-cell insulin secretions and lower glucose concentrations. Researchers are also examining the use of engineered E. coli gut microbes to treat obesity by synthesizing anorexigenic lipid precursors.¹

Additionally, modified Escherichia coli Nissle 1917 (EcN-GM) inserted into mice is showing the potential to positively affect obesity and the associated health risks, including food intake and hepatic weight.⁶ And, the treatment of diabetes may be revolutionized with the study of light-controlled optogenetics, where light is directed to activate desired cells or genes, reducing the risk of crossreactivity that can be found with chemical inducers. Opto-human embryonic kidney (opto-HEK) cell studies in mice with experimental type II diabetes showed blue-light-sensitive proteins produced an insulinogenic hormone that improved blood glucose levels. Another kind of therapy, LightOn, is a photo-switchable system that enables expression of insulin and improves blood glucose. Far-red-light controllable designer cells are also being studied for their ability to express GLP1.⁷

Drug Innovations and Vaccine Development

Synthetic biology’s use in reverse vaccinology is well-recognized as a scalable and sustainable approach to drug development — particularly after a fully synthetic mRNA vaccine for the COVID-19 virus was in design within days of the virus’s genome release, and emergency use authorization was granted just 11 months later.

Synthetic biology and reverse vaccinology are also being used in the development of personalized cancer vaccines and treatments thanks to proprietary immunogenic neoantigens and sequencing algorithms that define genomic mutations in sequenced tumors when compared to reference genomes. In particular, this technology is showing promise in pancreatic and melanoma cancers.⁸

Emerging innovations in cell-free protein systems may provide for rapid vaccine production at a fraction of the cost of traditional vaccines. With cell-free protein synthesis, transcriptional and translational cell information allows for protein production without the need for living cells, eliminating many challenges of traditional vaccine development.⁹

Therapeutic genetically engineered bacteria may also become a cutting-edge new treatment as biomarkers sense their control over the timing, localization and dosage. In mice studies, gene circuits are proving flexible, sustainable and predictable as candidates for treating some cancers, particularly when combined with synthetic surface adhesions targeted to bind to cancer-specific molecules.¹

Artificial Intelligence and the Future of Synthetic Biology

The addition of artificial intelligence (AI) to the field of synthetic biology exponentially expands opportunities for medical innovation to seemingly endless possibilities. Moving from the early days of predictive protein structure from amino acid sequences to today’s use with predictive physical outcomes of nucleic acid sequences, development times have shortened and complexity of achievable biodesign has expanded. AI’s ability to process large and precise datasets enables it to quickly identify research candidates, design laboratory studies for those candidates, uncover hidden patterns and regulatory elements, and model and predict behaviors all while analyzing results. Because AI is so powerful, it can not only decrease the length of time required for research, but its predictive abilities help reduce laboratory testing time requirements and thus innovation costs.10 It can also improve scalability.

However, use of AI is not without risk, particularly the risk for engineering a harmful sequence that spreads uncontrollably. This dual-use dilemma poses a very real biosecurity risk. Whether that threat is an undetected flaw in data algorithms or the intentional misuse of that data by nefarious persons who aim to exploit and harm, audits, transparency and accountability will help filter potentially dangerous risks.

Proactive awareness of risk is especially important in these early days as an industry-wide regulatory policy framework lags innovation, creating incomplete oversight.

AI’s immense power must never take the place of ethical judgment and human stakeholder intervention at every level to ensure responsibility, transparency and regulatory conformance, all without stifling scientific breakthroughs. Differentiating AI’s routine tasks from nonroutine decision-making is key.

Ethical Considerations

As synthetic biology capabilities grow, so too do ethical questions, particularly as desired outcomes vary across communities and countries. This synthetic life created for therapeutic purposes is so new, so rapidly evolving, that it has become entangled with broader societal questions and concerns.

Is gene optimization preferable to natural order? What do we know of patient safety in a field where longterm outcomes are yet unknown? Can this technology be used equitably across the healthcare system? How should the dual-use dilemma be addressed? All are difficult challenges, particularly as technology advances more quickly than policy debates and decisions.

Unintended consequences and unpredictability of synthetic biology is a real concern, and despite science’s best efforts to study and predict, there are questions as to whether harmful side effects or worse might affect patients. In the excitement of a new experimental treatment, even with informed consent, sometimes decisions are made before all of the facts are at hand.

Equity and access to care are always concerns in the innovation space as well. However, as synthetic biology is further studied and understood as it comes online and becomes mainstream, the expectation is a lowering of costs and speeding up of production. Even the fact that synthetic cells may not need the refrigeration like human-derived products do is a potential win for production and delivery. In the short term, like any new healthcare innovation, the risk of global disparities is real. In the long run, however, there is real and positive potential for a costeffective, scalable solution for many of today’s challenges.

The dual-use dilemma of a technology created for good, but one that could also cause harm, is a grave concern, so much so that the World Health Organization and other nongovernmental organizations have highlighted these issues and called for regulatory policy and oversight, particularly for AI in the bioengineering space.¹⁰

Even so, the possibilities for synthetic biology are exciting, and much work continues to improve methods and technologies that will one day enable engineered cells to advance into viable therapeutic treatments.