Proponents of synthetic biology introduced in molecular biology a number of principles directly inspired from engineering. Their goal: alter living organisms to make them produce new molecules. Numerous applications are expected in the areas of health, energy, materials, environment and agriculture. How will the transition to the industrial phase take place? This, today, is the main issue.

The early days of synthetic biology were primarily an ideological revolution. Its origins date back to the mid-nineteenth century, with the advent of evolutionary theories on one side, and, on the other side, the transformation of agriculture, which went from a mere practice to a science. The world of biology, and more broadly our conception of living beings, underwent a profound change from that moment on.

The emergence of biochemistry then reconciled the study of living organisms with that of compounds. The term “biochemistry” appears at the end of the 19th Century and indicates an increased interest in chemical reactions at work within the living: energy production by the cell, synthesis or reverse degradation of molecules… the better understanding of the chemical mechanisms at work in living organisms soon involved the notion of both an intervention and alterations.

The American botanist Luther Burbank then started to compare plant breeding to “architecture.” Stéphane Leduc, a French physician from Nantes, introduced in 1921 the term “synthetic biology.” The synthetic method, he wrote, “seems to be the most fruitful, the most likely to reveal to us the physical mechanisms of life phenomena whose study is not even sketched.”

However, it was not until the 1950s and 1960s that synthetic biology began to be considered from a technical point of view, through the development of such tools as the electron microscope that enabled dramatic advancement in the understanding of biology at the molecular level: among these is the discovery of DNA in 1953.

Meanwhile, it appeared more and more obvious that even though evolution works randomly, mathematical principles ruling biological networks are discernible. Then at the end of the 1990s, the rise of the biology of the systems offers a fertile ground which a number of engineers began to focus their attention on. Their motto: What I cannot create, I do not understand, a famous saying from physicist Richard Feynman, heard during one of his lectures at Caltech.

At the turn of the century, Drew Endy and Tom Knight laid the foundations of synthetic biology as we know it today. iGEM, the student competition they launched in 2004, proved crucial for the development of synthetic biology and contributed to the latter being introduced in France in 2007 at the Centre for Interdisciplinary Research in Paris. It is by participating in this competition that many researchers were introduced to this emerging field.

Proponents of synthetic biology introduced in molecular biology a number of principles directly inspired from engineering: modularity, standardization and abstraction. The concept of “BioBrick,” a standardized DNA sequence easily reusable and presenting a characterized behavior, being an emblematic illustration.

Small living factories
Synthetic biology is both Cartesian and reductionist. But too radical a simplification of biology can lead to overlook some of the “tricks” found by living organisms in the hundreds of thousands of years of development, tricks that would teach us interesting lessons.

Living organisms are remarkably effective. For example, the cell components are strictly organized in space, with a diversity of compartments called organelles. Many bacteria specialize these micro-compartments in certain metabolic reactions, thus increasing the productivity of the relevant enzymatic pathways. One can easily understand how interesting it would be to artificially control the spatial organization of these metabolic pathways.

This is where DNA nanotechnology comes in. This area uses the DNA bases complementary to design sequences assembling in an orderly manner at the nanoscale, in predefined patterns: nanowires, structures in two or three dimensions. Would it be possible to use the knowledge of this science to build artificial “organelles” to isolate any metabolic pathway and thus increase accuracy and performance?

Building a bridge between nanotechnology and synthetic biology is not an easy task. First, DNA nanotechnologies were previously only test tube science. How to manage simultaneously all the assemblage principles acquired in this field by 20 years of in-vitro experimentation, to make it work in-vivo? Then, how to work with RNA instead of DNA? RNA can be produced in large quantities in bacterial cells but poses a stability problem. Finally, how to characterize these structures in vivo? When venturing on the unpaved roads of science, new techniques for exploration often have to be developed.

Working at the frontier between so many areas requires the development of new ways of experimenting and thinking science, but also poses some regulatory issues which impact on ethics which – although we will not discuss them now – must be debated.

But the main challenge now is of technological and industrial nature. Because, beyond its didactic aspects, synthetic biology aims to divert microorganisms metabolism, to turn them into small living factories.

These factories have the particularity to accomplish amazing chemical reactions in physical conditions (temperature, pressure) much more reasonable than those necessary in the vast majority of conventional chemical syntheses found in the industry, at a much lower energy cost. Some microorganisms can also use waste from our industries (cellulosic waste, for example) or even directly use solar energy and exploit carbon dioxide. Finally, you will never see a factory create a perfect copy of itself – which biology does perfectly!

By mobilizing the resources of biology, we may radically change the equation of a number of problems, particularly in the energy field.

For example, the dependence on fossil energy resources represents a major geopolitical and climate challenge for contemporary societies. Last generation biofuels – which do not compete with food resources – offer an interesting solution to relieve present and future energy crises.

Hydrogen production is also to be considered, since hydrogen is an energy four times denser than bioethanol and the use of which emits only water. The hydrogen molecule can be produced biologically via different enzymes by testing a combination of enzymes taken from this wonderful “App Store” called nature. A well-known bacterium (Escherichia coli) allows the synthesis of bio-hydrogen; in his doctoral thesis, Camille Delebecque  developed a synthetic RNA-based organelle, better organized and 48 times more efficient than that of nature.

Syn-Bio-Cell

Industrial tracks
Synthetic biology thus opens the possibility of isolating the interesting metabolic pathways and increase their productivity, drawing it closer to industrial reality.

Similar applications already exist in the pharmaceutical, cosmetics, food supplements industry, as well as in regenerative medicine, waste treatment (with the creation of bacteria capable of degrading toxic substances in the environment) or agronomy (development of bio sensors to monitor soil nutrient quality…). Agriculture-wise, the manufacturing of insecticide necklaces or patches is being studied. Green chemistry and the production of biofuels are, of course, the first line: the American firm Craig Venter has signed agreements with Exxon and BP to develop microorganisms capable of continuously producing hydrocarbons (ethanol and butanol). Some figures have been heard: with an estimated market of 1,000 billion in 2025, synthetic biology may well be the future of biotech.

The transition to the industry is all the more evident as synthetic biology comes from a culture and an approach of specific biotechnologies, largely influenced by the world of engineering.

But this engineering culture opens up new opportunities, which should not be underestimated. Far from being confined to richly endowed laboratories with large pharmaceuticals and other firms barricaded behind patents, synthetic biology is also a cooperative discipline, leading to trades and more open forms of collaborative innovation. The application of engineering principles has enabled rapid growth, especially through some pieces of DNA easy to exchange and build, based on the work of others. These dynamics can be a strong dissemination factor and foster economic development.

This is the challenge of a firm like Synbio Consulting, aimed to facilitate the contribution of people not directed belonging to the small circles of specialists, but still able to identify potentially useful functionalities. It could concern especially farmers of developing countries who intimately know the resources available in their habitat.

Institutions as diverse as the WHO, the Bill & Melinda Gates Foundation and the American Academy of Sciences have recognized in recent years the synthesis of biology’s ability to contribute to the development, contributing to the development of new drugs, vaccines or antibiotics. To bring out knowledge and help nurture entrepreneurial projects, local ecosystems can be created and structured in the same pattern as the iGEM competition, or in a collaborative perspective similar to DIYbio movement.

The “Do-It-Yourself Biology” is a movement that aims to disseminate the skills needed to further biological engineering, relying in particular on the development of laboratory equipment at low cost, the establishment of community labs, and a collaboration with activist scientists from the iGEM community. The challenge is to make synthetic biology a field discipline, which can raise local solutions and, if relevant, be disseminated globally. We are not talking about mere dreams, but rather about ongoing projects, such as the development of a biosensor to detect the contamination of milk with melamine (a serious problem in China), a bacterial detector against arsenic contamination, or a low cost malaria diagnosis system.

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Synthetic biology addresses the next stage of its development into two very different forms: an industrial R&D full of promises for companies – startups or giants – which will control its potential; and a nebula of collaborative innovations disseminated throughout networks, institutions and major foundations. Who knows what lies ahead ten years from now?

This article was written with the help of Camille Delebecque, a scientist and entrepreneur in the field of synthetic biology.

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