The ultimate challenge of synthetic biology

The most astonishing scientific breakthroughs and the greatest increase of knowledge within the past decades have arguably occurred within the life sciences, the branch of science concerned with the principles and processes in living systems. Following the genetic revolution, researchers have accumulated an enormous and ever-increasing knowledge of the vast set of molecules and their complex interactions in living cells and organisms. This knowledge has led to the possibility of modifying these interactions and thus engineering living systems, yielding an exciting new area of science and technology called synthetic biology. Synthetic biology signals a new era for humanity, in which biology has become an engineering discipline. The animate world is no longer merely a fascinating study object but a resource offering mankind unprecedented opportunities to tackle the huge challenges in health, energy, the climate, and more. Despite being a relatively new research field, today synthetic biology is exponentially growing and already leading to unprecedented insights into how living organisms function.

Remarkably, however, in spite of our increasingly precise understanding of the details of life, we still face very basic open questions in biology and some of its fundamental principles still lie in the dark. We intuitively distinguish a living from a non-living system, and we can formulate necessary features of life such as metabolism and self-replication. Yet, despite a century of research, we still cannot satisfactorily define life or formulate a predictive theory of how it may spontaneously emerge from its non-living constituents, as would be required for a truly fundamental and quantitative understanding. It is unknown what physical laws account for the self-assembly, self-organization, and subsequent complexification of living systems. Indeed, the origin of life – when the first cells emerged out of molecular components on the early earth – is one of science’s greatest remaining enigmas. In other words, while we have acquired extensive knowledge about the molecular building blocks that form the basis of modern cellular life, we do not understand how these building blocks collectively operate to define life. Thus, the major scientific challenge of the 21st century is to combine our exquisite knowledge of the post-genomic era with the cutting-edge technology provided by modern physics and chemistry to address one of the oldest questions of mankind: what is life? The associated pursuit of simplified life forms, engineered life forms, and life forms based on components not found in nature are potentially of enormous value to applications in a broad variety of areas.

Can one build a living cell from individual molecular components?

To address these daunting riddles, we advocate an experimental bottom-up approach, where the aim is to reconstitute a living object by putting together individual molecular components and have them interact to form a functioning synthetic cell. As the cell is the smallest unit of life that we know, the primary goal is to assemble a minimal cell-like object from the smallest possible number of basic components, or better: to have them self-organize into a synthetic cell. This entity must satisfy, point by point, the defining elements that we minimally ask for in all life forms: 1. The existence of an information carrier, 2. A boundary that defines the cell and separates this information-carrying molecule from the environment, 3. Metabolism to maintain its internal energy balance, and 4. Growth and reproduction to produce a next generation of cells. Once such a minimal cell is achieved, a next step would be to include variation and error correction to guarantee a minimal amount of robustness and evolvability needed for long-term stability under varying environmental pressures.

The prospect of creating synthetic life has inspired scientists for many years. For example, recent progress by Craig Venter’s group has demonstrated that synthesized genomes containing several hundreds of genes can program viable cells. However, while this top-down approach of creating a minimal cell by selectively removing components from wild-type genomes has been highly successful, it does not reveal how the remaining gene products act together to create life. For example, the functions of 30% of the genes in Venter’s most recent minimal cell (Science 2016) remain unknown, leaving open essential questions on the inner workings of these cells. In fact, it has not yet been possible to rationally design and construct, bottom-up, a simple form of life-based on a limited number of building blocks.

Importantly, in recent years, tremendous progress has been made in the bottom-up reconstitution of basic cellular machinery. Following a strong push for quantitative studies of individual building blocks driven by the fields of biophysics and biochemistry, there has been rapid progress in the reconstitution and quantitative understanding of biological systems and processes such as complex membranes and transport systems, sophisticated DNA processing machineries, complex cytoskeletal systems, self-organized spatial protein patterns, cell-free gene expression etc. In parallel, the possibilities for genome engineering have exploded with the development of tools such as CRISPR technology. All these rapid advances in biophysics, biochemistry and genome engineering make it possible to take on the challenge of integrating basic individual systems into biologically functional entities and to embark on the ultimate quest of building a synthetic cell. We believe that the rise of synthetic biology now provides a viable route to address synthetic life, which makes it one of the most outstanding scientific projects thinkable.

Beyond basic science

Building a synthetic cell will not only answer one of the fundamental questions in science, namely “how life works”. It will simultaneously lead to a new technological revolution, with a huge impact. In a way, this can be compared with the invention of computers where pioneering scientific discoveries in the mid-20th century paved the way to personal computers and the internet. A more profound bottom-up understanding of life will yield a range of intellectual, scientific, and technological rewards. It will even raise fascinating philosophical and ethical questions as it impacts our fundamental understanding of the nature of nature, including living entities. Such questions intrigue the general public and scientists alike, opening up new prospects for valuable and dearly needed humanities-science dialogues.

In synthetic biology, it is now possible to engineer genetic circuits, biological modules and synthetic pathways. These will increasingly be used to re-program organisms to generate a whole range of products that will impact our society enormously in all aspects: from healthcare (cheaper drugs and targeted, non-invasive therapies for e.g. cancer, antimicrobial resistance, malaria), to energy (environment-friendly fuels); from agriculture and food safety (biological control of pathogens and biosensing) to new biomaterials with bespoke mechanical or electronic properties produced by bacteria in a sustainable way. The path towards a synthetic cell will similarly boost the development of unprecedented new application areas.

Synthetic biology has already captivated the interest of industry. Businesses increasingly recognize the potential of synthetic biology (especially top-down synthetic biology, see Figure below) in terms of applications and have demonstrated interest in this research field. Pharmaceuticals, food, nutrition, self-healing materials, bioplastics and sustainable fuels are merely a few examples. Unanticipated applications will surface once a synthetic cell based on a bottom-up approach is realized and next-generation synthetic cells will evolve from the initial prototypes. Designer synthetic cell systems undoubtedly will find their use as mini-reactors in biotechnology, nanodevices, biorefinery, environmental remediation, and health.

Taking a lead in Europe

Establishing synthetic cells from individual molecular components is one of the greatest scientific challenges of our time. It requires a large-scale interdisciplinary effort that unites the highest expertise and experimental research activities of various disciplines: physics, chemistry, engineering, and obviously synthetic biology. At the same time, the path itself towards the synthetic cell will open up entire new areas for applications, from bioengineering to nanomedicine. We foresee that the first realizations will be achieved already within 10-20 years.

Europe has a large number of the world’s top researchers who are currently working on different aspects of synthetic life rather independently. Recently a group of top European scientists from biophysics, biochemistry and synthetic biology started a dedicated European community with the common ambition to engineer synthetic cells using a bottom-up approach. This initiative for the moment includes researchers from the Netherlands, Germany and the UK. But this is only the beginning, as Scandinavia, Italy, France, Spain, Italy, and Switzerland are also very active and eager to embark on this challenge. It is clear that Europe harbours ambitious scientists who are leaders in their respective fields. Together they would be in a fantastic position to lead a synthetic cell project that will shape the field worldwide.

A major synthetic cell research effort would provide a unique opportunity to position Europe as a world leader in synthetic biology. Discussions have been initiated to start a European FET Flagship on the development of synthetic cells. Indeed, the synthetic cell is a flagship-worthy challenge. Developing a synthetic cell technology requires a concerted effort from biologists, chemists, physicists, engineers, mathematicians, and scholars from the ethics and humanities. A synthetic cell flagship likely is the only instrument that will allow us to address this formidable scientific challenge and to fully exploit the technological opportunities that it will generate – putting Europe at the forefront.

This forward-looking symposium aims at exploring the scientific challenges, technological opportunities, and societal impact of synthetic cells, and will discuss how Europe can position itself to take the lead.