Synthetic biology

About the authors: Anne Ingeborg Myhr, SVP Biotechnology and Circular Economy, and Odd-Gunnar Wikmark, Research Director, NORCE. 

Introduction

In 2003, the polio virus became the first living organism to be synthesised in a laboratory setting.  
 
Then in 2010, the first bacterial chromosome was recreated at the Craig Venter Institute in California, using digital data that detailed the genetic material (DNA) of a bacterium called Mycoplasma mycoides. This laboratory-created bacterium, popularly known as Synthia, proved that scientists can synthesize DNA and insert it into a cell, enabling it to function. 
 
Research and innovation in this area have led to what we now call synthetic biology. There are numerous definitions of synthetic biology. The Convention on Biological Diversity (CBD) describes synthetic biology as a further development and new dimension of modern biotechnology that combines science, technology and engineering to facilitate and accelerate the understanding, design, redesign, manufacture and/or modification of genetic materials, living organisms and biological systems. 

Synthetic bacteria - research and applications

In synthetic biology, genes and gene sequences are called building blocks or «biobricks» that can be rearranged and assembled in new ways. This approach has unlocked opportunities to deepen our understanding of cells and how microorganisms and complex biological systems, like organs, work. By combining genes and gene sequences in new ways and even synthesizing them in the laboratory, researchers can now engineer entirely new biochemical and chemical reactions in bacterial and yeast cells.

Recent years have seen major advances in genetic engineering tools in the laboratory and our understanding of genomes and genes. These developments now allow us to modify and design small living organisms, like bacteria, yeast and fungi. This progress has been made possible by machines that help us analyse an organism’s genetic structure and regulation (DNA sequencing) and machines that can create and assemble DNA into genes (DNA synthesizers). Breakthroughs in bioinformatics have played a crucial role in establishing synthetic biology as a dedicated field of research. With new tools like CRISPR and other gene-editing technologies, alongside machine learning, the pace of innovation in synthetic biology is expected to continue to accelerate.

There are two main approaches in synthetic biology: bottom-up and top-down. Until now, the top-down approach has been the most widely used, focusing on genetic engineering and genetic modification (see Genetically modified organisms). For genetically modified organisms (GMOs), this approach involves more extensive changes, including the use of synthetic gene sequences. By using synthetic biology to modify an organism, we can engineer new products (medicines, new energy sources and new materials) and produce known substances more efficiently and in a more environmentally friendly way. Today, modified bacterial and yeast cells are used to manufacture specific chemicals, enzymes, antibiotics and drugs. Examples include products that were once sourced from plants, such as the flavouring agent vanillin, and the malaria treatment artemisinin, as well as natural enzymes used in diagnostics, research, detergents and various industrial processes. Synthetic biology is also being used to develop medical products that were once derived from animals, such as blood factors. There appears to be major potential to reprogram cells to perform new functions. For example, research on mice has created synthetic kidney cells that detect blood glucose levels and produce the right amount of insulin, which could one day restore insulin production in diabetes patients.

Synthetic biology is also being explored as a way to replace products sourced from endangered animals, such as rhino horn. While 3D printing and other techniques are already being developed for this purpose, it is still unclear whether these new products will help reduce the trade in endangered species or potentially drive up demand. Researchers are also working on modifying algae to harness solar energy more efficiently and produce various oils. In industrial biotechnology, renewable sources such as methane, food waste and sugar production residues are being used as feedstocks to grow bacteria or yeast that, with the help of synthetic biology, can be engineered to produce custom biofuels or other specific products like enzymes and single-cell proteins.

Synthetic gene sequences can also be used independently, without first being inserted into yeast or bacterial cells. These are copies of gene sequences that already exist in plants, microorganisms or animals, but are now created by machines. Synthetic gene sequences are contributing to research, such as in advanced cell cultures, to gain a better understanding of diseases and in vaccine development. For example, the research behind some COVID-19 vaccines (mRNA vaccines) used synthetic gene sequences directly in the vaccines. These synthetic gene sequences will make it possible to develop new medicines faster and more efficiently and could also drive the development of personalised medicine.

In the pharmaceutical industry, synthetic biology is also used to create diagnostic methods that can detect specific substances, such as those present in cancer cells. The same approach can also be used in ecotoxicology, where modified bacteria act as biosensors, emitting light when exposed to environmental toxins.

In addition, synthetic gene sequences can be used in de-extinction efforts, where extinct species are revived by inserting DNA into egg cells (for example, from frogs) and by using surrogates to develop embryos. This approach could also help preserve endangered species by enabling reproduction without requiring individuals of the same species.

The other approach in synthetic biology is bottom-up, which was the method Craig Venter and his team used to create Synthia. This method is far more complex than top-down, as it involves designing specific gene products by assembling only the essential genes in a minimal synthetic cell that serves as a production or model system. For example, advanced cell cultures (organ-like structures) can be used as models to study embryonic development or disease. This approach involves pre-designing the types and numbers of stem cells used, along with the mechanical and/or chemical environment they require. Artificial genetic material (xenobiology) can also be created to form synthetic membranes or combined with natural genetic material to produce entirely new substances. By combining genetic material in completely new ways, with or without artificial genetic material, scientists can create new types of bioplastics and antibiotics. While we currently lack the knowledge to create fully synthetic life, advances are happening quickly.

Despite the high hopes for synthetic biology, uncertainties remain around potential unintended effects of creating and using these completely new products. Even though we know a lot about individual genes and their properties and have methods to assemble them, we still lack a full understanding of the incredible intricate interactions between genes. New combinations of genes and gene sequences, and the ways these are impacted by and interact with their environment, could add further complexity. With entirely new gene sequences and completely synthetic genes, we are entering uncharted territory – since these are not compatible with known organisms. What really happens in a cell when we introduce novel genes? Can we predict the novel compounds that might be created? Are we “playing God” by altering life or even creating it? Are we being reckless? Could synthetic biology lead us to a mechanistic approach: – viewing nature as a machine, an industrial platform for producing whatever we want, whenever we want? Such fundamental biological, ethical and even religious questions need careful consideration if we are to use this new technology to tackle important societal challenges or to address human-made problems. We also need to ask: Could using this technology solve some problems while creating new ones? Ethical concerns relating to responsibility, unforeseen consequences and the potential for «dual use» are particularly relevant for researchers.

Synthetic living organism – dual use

The first synthetic living bacterium, Synthia, was created from natural genetic material without introducing any novel genes. Synthia proved that life can be built from scratch in the laboratory from a bacterium. This presents new opportunities – such as assembling amino acids to build genes or DNA fragments that do not occur in nature. While these advances may be aimed at solving societal issues, they could also be used in more problematic areas such as military research and (bio)terrorism.

Concerns around bioterrorism also stem from the possibility that knowledge gained through virus and bacteria research could be used for harmful purposes. «Gain-of-function» research is already underway in laboratories to develop effective vaccines by adding or modifying gene functions in viruses. This will help scientists understand how viruses cause disease and evade the immune system, and the natural limits of their spread. One hypothesis regarding the origin of the COVID-19 virus was that it emerged from such research, though this remains unproven. Viruses like the polio virus and horsepox virus have already been recreated in laboratories. This demonstrates that even dangerous viruses can be built or recreated, potentially for harmful purposes.

This dual use raises ethical questions around who should be involved in evaluating whether a research project’s goals and methods align with broadly accepted values (see Research and society). It also places responsibility on researchers to ensure rigorous laboratory security in order to prevent synthetic organisms from being released or stolen. Transparency is essential and closely tied to accountability.

Socially responsible innovation and the precautionary principle

Who are we developing new technology for, and for what purpose? Which resources should be invested, and who decides how they are used? These are important ethical questions in research. With emergent technologies, we have a chance to address these questions before significant funding is committed and before projects are launched. Since emergent technologies can be applied in both beneficial and harmful ways, including a broader set of stakeholders than researchers, such as those who will ultimately use the technology, could help highlight both opportunities and potential risks. This approach to responsible innovation could help steer product development and use towards solving societal challenges with minimal risk. It is especially relevant for research and innovation in synthetic biology.

Synthetic biology holds promise for numerous applications, but uncertainties about its potential environmental and health impacts have led some to urge the need to adopt a precautionary approach. There is no place for generalisation here. Each case needs to be evaluated individually, since the complexity and level of control vary between the various technologies used to create synthetic products. These assessments should also consider the intended purpose of each product. Today’s synthetic products are typically either advanced GMOs or based solely on synthetic gene sequences. In the future, we are likely to see more examples of synthetic life, like Synthia, which will be more sophisticated and designed for specific functions. Since synthetic biology is still a novel technology, we have an opportunity to conduct precautionary research while developing new products and processes, ensuring that innovation goes hand in hand with health and environmental safety (see also Risk and uncertainty). This approach will also contribute with more knowledge about how synthetic products interact with their surroundings and impact health, informing future decisions on their commercial use.

How we regulate synthetic biology is an important issue. Top-down approaches in synthetic biology are covered by existing genetic engineering laws. However, there is some debate as to whether these laws are entirely relevant or capable of adequately assessing the risks of more complex synthetic organisms and products, especially since we often lack similar organisms for comparison. And what about entirely new life forms, like Synthia? Using synthetic biology to revive extinct animals also raises some totally new questions such as should we consider such animals invasive species? How might their introduction impact existing species and ecosystems? There is also ongoing discussion about whether researchers should self-regulate the field by establishing a code of conduct. However, self-regulation can pose ethical challenges; many researchers may struggle to balance their enthusiasm for advancing emerging technologies with a critical examination of potential social, environmental, and health risks.

Patents

Commercial exploitation of genes and gene sequences becomes a particularly relevant issue in light of developments in synthetic biology. Patents are regarded as beneficial since they promote innovation and the development of new products and processes. Synthetic biology partly circumvents the debate associated with biotechnology and genetic engineering where the value-based criticism «life cannot be patented» has raised the question of rightful ownership. Synthetic genes are made with the help of a machine, but may be a copy of something found in nature. Patenting in the field of synthetic biology may lead to less transparency (see also Research ethics and patents) and to inequity since low-income countries do not have the knowledge or resources to create or purchase synthetic products The research ethics complications of patenting of processes and products based on synthetic biology should therefore be investigated more closely.  The same applies to initiatives to promote transparency around research in connection with synthetic biology, such as the iGEM and BioBricks initiatives, where knowledge and data is openly shared.

References

Bioteknologirådet (2023) Syntetisk biologi. Available here (only in Norwegian): https://www.bioteknologiradet.no/temaer/syntetisk-biologi/

Convention of Biodiversity, Synthetic biology, CBD Technical series no.100 (2022). Available here: https://www.cbd.int/doc/publications/cbd-ts-100-en.pdf

Mathur, Neha (2022) What is Gain-of-Function research? News Medical Net. Available here: https://www.news-medical.net/health/What-is-Gain-of-Function-Research.aspx

Parens, E., Johnston, J., Moses, J. Ethical issues in synthetic biology, Hasting Center Report, June 2009. 

This article has been translated from Norwegian by Samtext International AS.