The FDA needs to get ready to evaluate synthetic cells, the next generation of therapeutics

Expanding new medical treatments requires pushing — and sometimes breaking — the boundaries of what currently defines therapeutics. One of those boundaries is the very definition of a cell.

Until recently, cells were all-natural beings, living cell begetting living cell. That’s changing as synthetic biologists and engineers are learning to create synthetic cells that may someday change how a range of diseases are treated.

Synthetic cells are membrane-enclosed systems constructed from nonliving parts. They can contain engineered genomes, artificial organelles, and complex enzyme pathways. Acting as microscopic bioreactors, they present opportunities to design and deliver medicines that uniquely match an individual’s DNA and disease profile.

Researchers across the U.S. and around the globe are advancing the understanding, development, and use of synthetic cells. Yet the Food and Drug Administration (among other regulators) has not yet begun to develop a regulatory framework for artificial cell technologies. Such lack of preparation for what could be the next forefront of medicine could largely delay the development of these therapies.

Synthetic cells on the frontier of medicine

Despite tremendous recent advancements in science and biomedicine, no living cell is fully understood. Although a toolbox of theories exists to understand general mechanisms of cell functions, so far there’s no recipe for creating a living cell. Because no one completely understands how cells work, it’s difficult to anticipate how living cells react to different environments and how they — and a host — will respond when they are used as therapeutics.

Knowing that no two individuals share the same DNA and that the human genome is highly susceptible to mutations from environmental cues, we and others foresee a need for personalized therapeutics that may be difficult to create using live cells. Because synthetic cells are far easier to design and manipulate to target unique DNA sequences, however, they may be able to better meet the need for precision medicine to address existing gaps in health care.

Synthetic, non-living cells have advantages over natural cell therapies. They’re easier to manipulate and redesign, and their simpler biochemical frameworks and hand-selected biomaterials make it possible for them to more accurately target cells, tissues, and pathogens. Synthetic cells’ unique and dynamic anatomies allow developers to pick the necessary components and remove cellular debris that may trigger adverse biochemical reactions in the body, creating precise tools whose every part has an understood and prescribed function.

Creating a biologically produced drug currently requires that live natural cells, like bacteria or yeast, be cultured in large bioreactors. Because live cells have highly complex genomes, it is difficult to insert a new metabolic pathway into them. Given the time and effort needed to create each manufacturing strain, this is practical and economically viable to do only for drugs required in large quantities.

Synthetic cells, though, have far simpler genomes that are much easier to engineer. This may allow for the production of custom drugs on demand in smaller doses for smaller groups of patients, or even for individuals. With synthetic cells, scientists could create on-demand vaccines to protect populations against viruses, or unique drugs to treat rare infections. Synthetic cells can also be used to treat cancers on a personalized level, so the drug a cancer patient takes is designed to specifically treat their cancer’s exact genome.

Synthetic cells are complex enough that they can be used for precise applications, but simple enough to not be capable of evolution leading to off-target interactions. In this way, synthetic cells combine the advantages of live cell therapeutics like bone marrow transplants and chimeric antigen receptor (CAR-T) cells with those of single-component biologicals and small molecule drugs.

In addition, their relative ease of use and room temperature storage enables point-of-care applications, making it possible to deploy cutting-edge therapies in places where maintaining a cold chain is challenging.

Addressing gaps in regulation

While synthetic cells could someday be powerful tools to advance medical care, no legislation currently exists to specifically regulate this technology.

Developers of synthetic cell therapies can proactively address current regulatory gaps by following practices pharmaceutical companies have previously used with similar engineered bioproducts such as CAR-T cell therapy, the first of which gained FDA approval in 2017, representing a milestone in artificial — albeit living — cell drug development.

When the FDA began reviewing CAR-T cell therapies for approval, the agency encountered several roadblocks like those currently being faced by developers of synthetic cell therapies. At the time, documentation existed for cellular and gene therapies. But the FDA had no specific guidance for CAR-T products’ unique functionality. Developers approached this knowledge gap by engaging with the FDA. By setting up meetings with experts in the FDA’s Center for Biologics Evaluation and Research (CBER), they sought insight on proceeding with evaluating safety, designing clinical trials, and addressing manufacturing challenges. Seeking direction early in the development process also allowed regulators to consider co-molecules — the necessary chemicals needed for CAR-T cells to carry out their intended physiological reactions — within drug ecosystems.

Developers of synthetic cell therapies need to follow the same strategic approach: Engage with the FDA early, and begin to proactively generate plans for every step of testing and production.

Paving the pathway to FDA approval

Successfully bringing synthetic cell medicines to the market is doable only if researchers can foresee a pathway to FDA approval, which often depends on the answer to two major questions.

• Is there a need for this product?
• Do its potential benefits outweigh its risks?

Synthetic cell technologies offer several possible advantages to personalized medicine that living cells cannot afford, such as providing individualized programmability that could reduce harmful side effects, increase global accessibility to treatments, and reduce costs. Despite these advantages, it’s difficult to break into a saturated and competitive pharmaceutical market containing conventional chemical drugs and several effective living cell therapeutics.

One means to advance synthetic cell therapies is to focus on their potential to treat rare diseases. The 1983 Orphan Drug Act classifies a rare disease as one affecting fewer than 200,000 Americans. The act provides financial incentives to companies developing drugs to treat these diseases. Because synthetic cells can be built with such high levels of precision, this platform would be a good candidate for treating rare diseases. Taking advantage of the orphan drug path could smooth some of the bumps on the road to FDA approval.

While it is impossible to avoid the high initial costs of building the equipment required to construct synthetic cells, developers can secure financial support to enable such work. For example, the FDA launched the Emerging Technologies Program in 2014 to provide funding to build necessary manufacturing equipment, assisting companies in developing drugs that require new advanced manufacturing procedures. The FDA should consider launching a similar program to support emerging biotechnologies, including synthetic cells.

Security concerns and synthetic cell research

The synthetic cell engineering community strives to be an open global network through which researchers can publicly share ideas and advancements. But much like the early stages of the open-access internet, long-term security risks must be considered.

The synthetic cell engineering community largely practices open-source biology, meaning that all knowledge, research, innovations, and engineering resources are shared online on open access digital platforms. This is primarily beneficial to the field, as it allows scientists and non-scientists around the world to engage in synthetic biology and innovate faster. With open-source information, however, come security concerns. As information becomes increasingly accessible, it requires heightened need for protection. Putting genetic code or cell-assembly instructions online would hypothetically allow anyone anywhere to download genetic code from the internet and, with the right DNA synthesis equipment, build an organism or pathogen for nefarious purposes.

While these concerns may appear far-fetched, it would be unethical to begin using synthetic cells to create medications and medical devices without preemptively assessing where and when it’s safe to work with them. This work is already being done in the biosafety and synthetic cell engineering community, with assessments and analysis ready for the regulatory approval and development of new policies and practices.

New directions for new challenges

The development of synthetic cell therapies needs to occur in tandem with a focus on future FDA approval and safety. Before the first synthetic cell therapy enters human trials, plans and strategies should be in place for overcoming the limitations of the current FDA approval pipeline. Without that regulatory work, the future of these revolutionary therapies could be stalled, or even derailed.

Kira Sampson is a science writer in the Science Communications Lab at the University of Minnesota BioTechnology Institute. Carlise Sorenson is a writer and outreach coordinator for the international synthetic cell engineering initiative Build-a-Cell. Kate Adamala is a McKnight Land Grant assistant professor at the University of Minnesota and co-founder of Build-a-Cell, an open community supporting people working to build synthetic cells.