S ynthetic biology (often abbreviated as synbio) is a term that is more and more in vogue and used widely by scientists and the media. The name evokes images of sophisticated genetic engineering aimed at creating a bio-future filled with new life forms that are made and grown to help feed and clothe humanity and to keep us healthy and beautiful.

But what is synthetic biology really? What does the term mean today, in our bright & shiny, splendid and brand spanking new year 2020?

To answer this question, it is useful to take several steps back and examine the technological leaps that gave us the ability to change microbes (bacteria, yeasts, fungi and single-celled algae) to do our bidding. Figure 1 takes a simplified stab at this history.

1. Biotechnology was born tens of thousands of years ago, when thirsty ancestral humans noticed that sugars dissolved in water spontaneously fermented into alcohol. This happened because of the natural abundance of wild yeast strains that have evolved to be particularly efficient at turning sugars into ethyl alcohol (or ethanol, the same alcohol that most of us love to drink in the form of beer, wine and other spirits). The yeast gains energy and carbon building blocks in the process, and takes advantage of the toxicity of alcohol to other microbes that are competing for the same sugars. Natural fermentation with wild yeasts and bacteria continued relatively unchanged until the 19th century, when the microbial basis of fermentation (and disease) were discovered. These advances in microbiology led in a twisted path to understanding the genetic basis for heredity and traits, identifying the carriers of genetic information (nucleic acids in the form of DNA and RNA) and as a consequence…

2. The ability to change organisms by adding new genes into their genome. The molecular biology revolution of the 1970s allowed specific DNA sequences to be introduced into bacteria and propagated through molecular cloning methods. Techniques were discovered for identifying the base sequence of DNA molecules (the order of the four genetic letter A, C G and T) and identifying the functions associated with the proteins spelled out and encoded by genes. This set of breakthroughs greatly enhanced the capabilities inherited from early microbiologists which were largely limited to propagating microbes (‘bugs’ in lab parlance), mutagenizing them and crossing them to one another to produce changes by natural, sexual recombination processes. Molecular biologists suddenly had the power to deliver genes and functions into organisms where they were not naturally present, setting the stage for a dramatic acceleration of bio-production (i.e. human insulin produced in bacteria) and microbial evolution in the hands of man- and womankind. The process of moving genes around from one organism to another is referred to by biologists as genetic transformation (or transformation for short). Scientists, always eager to one-up ‘Dr Jones’ in the lab across the hall, quickly began to practice transformation at ever-increasing scales, which is how we gradually got to synthetic biology. And with that, our first glimpse of what synthetic biology really is – it is the wholesale and large-scale practice of molecular biology techniques, to transform a microbe as thoroughly as possible from a wild bug to a biological factory for producing something desirable for humans. As one of the logical next steps…

3. Biochemists specializing in the complex metabolic interconversions of compounds that happen within every cell, made it their goal to transfer a complete biosynthetic capability from one organism to another, creating the ability make compounds that were not present before. While a molecular biologist in the 1980s would have made it his goal to make yeast ‘better’ by increasing the efficiency of ethanol production, these metabolic engineers created bacteria and yeasts capable of producing specific new chemicals that are not naturally found in the biological world, but that are highly desirable to humans for making plastic, fibers and many other synthetic materials. However, metabolic engineering was not the end of the line, as these scientists quickly realized that transferring a new metabolic pathway into a bug might give it the ability to produce a tiny amount of a new compound, but would not make it very efficient at doing so. The optimization process of starting with a raw engineered cell and turning into an efficient bio-factory required fine tuning of the microbe’s metabolism and carbon flow, which in turn relied on many other changes to the microbial genome, many of which not directly related to the enzymatic synthesis of the target compound. And in this fashion we have arrived at…

4. Whole-genome cell engineering, which aims to use every relevant function present in a microbial cell to achieve the goal of efficient, economical production of a compound or material of interest. Understanding that biological systems are highly complex, intricate and fine-tuned systems of interrelated parts, biologists are now at a stage where the entire genome is our canvas, and we make potentially many changes in diverse parts of a genome to achieve a desired outcome. Craig Venter, in a series of daring and ambitious experiments, set out to create an entire microbial genome from scratch, with the ultimate goal of flexible and purposeful programming of the new organism to execute a single, useful task. Similar efforts are being taken to re-synthesize yeast with the goal of enhancing the biotechnological utility and flexibility of this remarkable organism (Yeast 2.0).

So what is Synthetic Biology? With this history in mind, how can we define synthetic biology and what does it mean ? Synthetic biology encompasses all of the molecular genetic methods developed during and since the molecular biology revolution, meaning parts 2, 3 and 4 in the diagram and text above. But the term also implies a large-scale implementation of these methods, and a more substantial transformation of an organism than the introduction of one or two genes. The pioneering molecular biologist and Nobel Laureate Paul Berg said it best when he called synthetic biology ‘molecular biology on steroids’. The field stands tall on the groundbreaking thinking and approaches developed by molecular biologists in the 1970s and 1980s. Our preferred way of using ‘synthetic biology’ is when referring to expansive applications of molecular biology for microbial engineering and improvement. In specific instances, synthetic biology can rely on synthesis of novel genes from scratch, designed with a specific purpose and adapted to the host organism. However de novo gene synthesis is not a requirement for the practice of synbio.

An excellent example of synthetic biology at work is Primordial Genetics’ transformative Function Generator™ technology, which is used to create millions of novel genes from sequences encoded in a microbe that are used as genetic building blocks. The collections of novel genes are sifted for the ones that improve a microbe’s productivity, resistance to stresses, or ability to make an unusual molecule. The novel genes allow us to impact the performance of a microbe in bigger steps that are possible with other technologies. Primordial Genetics has successfully applied Function Generator™ to engineer yeast and bacteria for improved production of alcohols, amino acids and proteins (therapeutic proteins and enzymes) and is using the same approach to develop enzymes with vastly improved properties.

As a final thought, synbio, the abbreviated form of synthetic biology, can also be used as a verb. As in: “Sabrina spent the last 2 weeks in the lab and synbio’d an amazing new yeast strain.” So if this piece has you curious and hungering for more, contact us with your goals and dreams. Come synbio with us!