Redesigning Organisms as Metabolism Architects

Abolis leverages synthetic biology to design biochemical pathways that enable rapid, cost-effective production of novel chemicals, including pharmaceutical starting materials, intermediates, and APIs. These biochemical pathways can be further coupled with appropriate synthetic organic chemistry or chemical process engineering to increase the range of potential products.

Why Metabolic Engineering?

As synthetic biologists, we redesign the metabolism of living organisms so they will produce large quantities of desired chemicals that can be used in the pharmaceutical, cosmetic, and agrochemical industries. The organism’s genome is engineered using rational approaches, by inserting large pieces of artificial DNA that direct the organism to produce a desired molecule from sugar or another cheap substrate.

In many cases, these chemicals can be produced at room temperature and ambient pressure in water. No potentially harmful or toxic solvents or chemical raw materials are required, and no dangerous waste is produced.

In some instances, biotechnology enables the production of molecular structures that cannot be accessed via traditional organic synthesis. This is especially relevant for drugs whose production requires hemisynthesis, such as steroids, analgesics, opioids, and some anti-cancer drugs. It also allows for the discovery and production of novel drugs via innovative bio-based, renewable, sustainable processes.

A Bio-Retrobiosynthesis Approach

It is common in organic chemistry to perform a retrosynthetic analysis to identify possible synthetic routes to a target molecule. To make retrobiosynthesis more feasible — and facilitate leveraging the greater sustainability of synthetic biology — Abolis developed computer algorithms to enable the identification of metabolic routes by researchers, which could be used to engineer the biosynthesis of any given molecule.

Bringing Metabolic Engineering Expertise to Chemical Companies

Abolis is derived from the Greek word metabolē, meaning change and transformation. The name also conveys the sense of the word abolition, or a progression from something undesirable to something better. Abolis Biotechnologies was created in 2014 and currently has 24 employees — the company has already worked experimentally on close to 20 different molecules. 

The first step taken as a company was to work on retrobiosynthesis software, but we quickly understood that, if we really wanted to help the chemical and pharmaceutical industries move toward synthetic biology and more sustainable manufacturing processes, we needed to develop additional capabilities — not in areas where our customers had expertise, but where they were lacking — such as in the genetic engineering of microbes and fermentation, including the analytical and robotic capacities required to support such development.

Abolis has developed — and continues to expand on — a portfolio of technologies for the design, construction, and scale-up of tailor-made fermentation processes for our clients’ molecules. We have learned that working in synergy with our clients’ teams is the best way to provide the right solutions for their requests and situations.

We understand where fermentation can be best leveraged and where it isn’t appropriate. Projects can begin with organic chemistry steps and end with bioconversions, or vice versa. We know where fermentation or enzymatic processes can provide access to molecular structures and/or levels of selectivity not possible with organic transformations. We also understand the limitations of synthetic biology and recognize when simple organic reactions will afford the optimum results.

Tackling Complex Chemical Molecules

One of the fundamental features of Abolis has been our ability to design lengthy routes to highly complex molecules. As far as we know, Abolis is the only company able to tackle such complex, larger molecules using synthetic biology — we also have the advantage of our bio-retrobiosynthesis approach, bioinformatic tools, and robotic platform capacity, which was intentionally optimized to enable complex pathways. As a result, Abolis has extensive experience with the design, implementation, and optimization of long metabolic pathways and specializes in custom process development for highly complex molecules.

Metabolism Architects

Architects convert building specifications into a real-life design. They understand the overall end-goal and use different high-tech tools to realize that complex structure, such as computer-aided design (CAD) software. At Abolis, we have similar responsibilities, but for the production of specific chemicals. We use our retrobiosynthesis capacity to research possible pathways using fermentation and enzymes and our knowledge and understanding of synthetic biology and its uses in collaboration with organic chemistry to determine novel biosynthetic or hemisynthetic routes. 

We look at the entire business case, including possible pathways and raw materials for producing the molecule, and consider the intellectual property surrounding those pathways. We also conduct a technoeconomic analysis, simulating what a manufacturing plant would look like and the performance needed to meet the target price and scale. We then devise a roadmap for making the specific chemical to fit these specifications, including the manufacturing process, the time required to construct the facility needed, how much risk the project will carry, and the potential return on investment in collaboration with the client team. 

Trading Longer Development Times for Scalability, Security, and Cost-Savings 

The development of processes that leverage metabolic engineering technologies often takes longer and costs more than those using only organic chemistry. However, those processes will be eminently scalable and readily transferable from one site to another. The facility and equipment will also cost less to build and install, because there is no requirement for high pressures or temperatures, and no hazardous waste management requirements. Operators also benefit from a safer work environment, and with increasing restrictions/bans on certain solvents and other chemicals, the need to change processes or install expensive containment systems is avoided.

Benefitting Drug Discovery 

Many modern small molecule drugs have been developed using combinatorial chemistry, which often results in complex molecules that cannot be readily produced using scalable processes. This philosophy can also be applied to biotechnology. As importantly, combinatorial biotechnology chemistry has the potential to identify novel chemicals or chemical mixtures that cannot be produced using classical chemistry and have not previously been accessible or explored, though scalability is more likely to be achieved. This approach may open up new avenues for drug discovery.

Focus on Yeast Fermentation

At Abolis, most of our work is performed using yeast — primarily but not exclusively Saccharomyces cerevisiae rather than bacteria. Many of the enzymes utilized for complex chemical transformations originate from plant, insect, or mammalian cells. These enzymes are usually better expressed in eukaryotes like yeast than in prokaryotes, which thus saves time and money in the enzyme and pathway development processes. Yeast offers more  possibilities for building long pathways and stabilizing genetic constructs than bacteria such as Escherichia coli and are more resilient to phage contamination and less prone to generate endotoxins.

Increasing Pharma Potential

The potential applications of synthetic biology in the pharma industry are manifold. In addition to enabling the cost-effective production of complex drugs and the synthesis of molecules not possible with organic chemistry, as well as expanding the chemical landscape of drug discovery, synthetic biology may also provide a means to economically produce known and promising phytochemicals that have not been pursued because their plant sources and/or extraction were impractical.

We also believe that our biotechnology program may be applicable to the synthesis of biologic drugs and provide an avenue for dramatically reducing their cost. While we are currently focused on highly complex small molecules, we strongly believe that in the future we will be able to impact biologics production by switching processes away from mammalian cells.  

Cyrille Pauthenier, Ph.D.

Cyrille Pauthenier is an entrepreneur in synthetic biology. He graduated from École Normale Supérieure in Paris and studied fundamental chemistry and biology with a focus on biomolecules modeling and engineering. In 2011, he specialized in synthetic biology. After obtaining his Ph.D., Cyrille co-founded the Abolis Biotechnologies company in 2014, with the aim of bringing state-of-the-art methodologies in metabolic engineering for the development of new microorganisms capable of producing chemical molecules by fermenting renewable resources.