Building Living Therapeutics With Synthetic Biology
Synthetic biology is powering living therapeutics and thermostable vaccines with engineered cells, precision circuits and AI-designed proteins.
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Synthetic biology is reshaping how we approach therapeutics. Using engineering principles in biology, it is possible to “rewire” cells by reconstructing the underlying biological code to create new functions and outputs.
Genetic circuits that already exist in nature and contain interacting genes for specific cellular functions are disassembled into smaller modular units, each with a defined input and output. This creates a modular framework in which these simple genetic “units” can be combined in different ways to form new circuits. These circuit designs can be made to control processes like gene expression, metabolism or detecting signals in the environment.
For decades, the development of new drugs largely relied on chemical synthesis to create small molecules as drug candidates. Significant progress in synthetic biology, particularly in its applications in biopharmaceuticals, means that creating “living therapeutics” by re-engineering genetic circuitry has the potential to tackle some of the significant unmet clinical needs of today. In the last decade, synthetic biology has rapidly transitioned from proof-of-concept ideas to real-world clinically relevant innovations, such as gene editing therapies, cancer immunotherapy and next-generation vaccines.
Engineering cancer-killing cells
The director of the University of California San Francisco (UCSF) Center for Synthetic Immunology, Professor Wendell Lim, has pioneered synthetic biology approaches for cell therapy to treat cancer and other complex diseases. His group has spearheaded research in CAR T-cell therapy, where a patient’s immune cells are genetically altered and used as a “living therapeutic” to direct an immune response against a specific target, like a cancer cell.
“CAR T-cell therapy works by putting new genes into a patient’s immune cells” Lim explained, “In most cases, this gene encodes a chimeric antigen receptor (CAR) that allows the T cell to recognize a cancer cell molecule – directing the T cell to launch a killing response. So, CAR T cells can be engineered to recognize and kill tumor cells that our immune systems normally do not. The CAR T cells, once engineered, are reinjected into the patient, allowing them to find and kill the cancer cells.”
This approach has been highly successful in targeting blood cancers. In 2017, the US Food and Drug Administration approved two CAR T-cell immunotherapies for clinical use in leukemia and lymphoma. Much of the research on CAR T-cell therapy today focuses on how it can be applied in the treatment of solid cancers, such as breast, lung and brain cancers.
“One major challenge is finding molecules to target these solid tumors that are absolutely tumor specific,” said Lim. “If the targeted molecules are found in normal tissues, there could be toxic side effects. It is also harder to get the CAR T cells to infiltrate and enter these solid tumors.”
Lim recently led a project that sought to address this challenge and find more sophisticated ways to target T cells to find diseased cancer tissue. Published in Science in 2024, the team created a set of brain-sensing T cells programmed to deliver customized therapeutics to the brain without causing off-target effects to non-diseased tissue outside of the brain.1
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“We were able to engineer a tissue ‘GPS’ system for T cells, whereby the cells can recognize when they are in the brain and limit their killing response to this organ,” explained Lim. “Using this GPS receptor in combination with a CAR allows us to get far more precise and effective targeting of challenging and deadly brain tumors, like glioblastoma.”
The team also investigated new ways to use engineered T cells to treat autoimmunity and organ rejection.2
“We engineered T cells that can recognize disease tissue,” Lim continued. “Instead of launching a killing response, they launch an immunosuppressive program that dampens our natural immune rejection of a tissue, like in type 1 diabetes or in the case of organ transplant rejection.”
Using synthetic biology to create living therapeutics represents a major shift in the way we treat complex diseases like cancer. Ongoing research into CAR T-cell therapy for solid tumors offers new hope to patients with otherwise difficult-to-treat cancer. Lim believes this approach will also expand into designing therapeutics for other complex diseases.
Advancing vaccine development
Synthetic biology is also being used to develop vaccines. The recent development and rollout of the COVID-19 mRNA vaccine highlighted that the synthetic biology toolkit offers several major advantages, including faster vaccine design and better adaptability to the evolving nature of disease.
“With synthetic biology, you have the possibility to design proteins bottom up. That has now changed the whole playing field and opens new possibilities for vaccines,” said Professor Imre Berger, director of the Max Planck-Bristol Centre for Minimal Biology at the University of Bristol.
mRNA vaccines use synthetic mRNA to encode viral proteins that would normally be produced by the pathogen. This is delivered to the cells, where it is translated into the corresponding protein to elicit an immune response, teaching the body to recognize and destroy the pathogen. Another approach is to use self-assembling virus-like particles (VLPs) to make structures that mimic the outer surface of viruses to trigger an immune response. VLPs are constructed by introducing genes into a host organism to express proteins designed to self-assemble into viral-like structures.
One of the biggest challenges in vaccine development is the natural degradation of vaccine proteins at room temperature and the dependency on refrigeration for storage and transport up to the point of vaccine administration (the “cold chain”). This is particularly prevalent for vaccines that need to be administered in developing countries and may lack the necessary infrastructure for cold storage and transport.
Part of Berger’s research focuses on using VLPs to create safe, nucleic acid-free vaccines that elicit a strong immune response. Working with a collaborator in Grenoble, France, the team researched an adenovirus-based VLP as a synthetic delivery platform to be used in a vaccine against Chikungunya disease.
After discovering that the VLPs arranged themselves into a symmetric and hollow dodecahedron shape, the team realized that the particle was also thermostable after accidentally leaving an Eppendorf tube in a lab coat pocket for six months. This was particularly remarkable, as the temperature in the lab could often reach 40 °C. Subsequent testing found that the particle was uniformly stable at 45 °C.3
For vaccine applications, this could remove the need for cold storage and make them much easier to distribute. The team also discovered that the protein was easy to functionalize, creating a versatile “plug and play” platform that could be used with a huge range of different protein epitopes, making it accessible for different vaccine targets. In recent work, the team has published a paper in Antibody Therapeutics using the platform to design a thermostable nasal vaccine against COVID-19.4
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What’s next for synthetic biology?
“I think that in the next 10 years, we will see an even more pronounced acceleration in AI and computation technology,” said Berger.
Artificial intelligence (AI) is already supercharging protein design and engineering. DeepMind’s AlphaFold accurately predicts three-dimensional protein structures from their amino acids, with recent research demonstrating how AI can be used to design entirely new proteins to neutralize lethal snake bites.5
Designing new genetic circuits in synthetic biology – an iterative process with extensive datasets – lends itself to AI. “It’s driven by two areas,” said Berger, discussing the use of AI in vaccine development. “AI is driven on the design side – where it has become a lot more convenient and accessible to design these kinds of nanoparticle vaccines – and on the side of upscaling. Intelligent design and computation can help a lot.”
AI can increasingly be integrated into every aspect of synthetic biology’s design, build and test phases. For example, the design phase can be expanded by using AI to design new genetic circuits and predict how the different components will interact.
The test phase, normally time-consuming and expensive, can increasingly be performed computationally and at a scale not previously possible without AI. This will help to reduce the bottleneck, limiting wet lab experiments to fewer and more thoroughly tested designs with a higher chance of success.
In the build phase, AI-driven automation systems will increasingly automate repetitive tasks in synthetic biology, such as cell culture and experiment monitoring. As Berger said: “I’m convinced that this AI revolution will give us more time to think again.”
