Overall Concept

Evolva's Genetic Chemistry approach is based on two separate, but intertwined, concepts. It is a disruptive technological approach to the creation of novel small compounds that differs sharply from the prevailing approaches of the pharmaceutical industry. In many ways it can be considered as an arm of synthetic biology.

Overall Concept 1 – Biosynthetic Chemistry

Modern chemistry is associated with organic synthesis – But whilst synthetic organic chemistry has a proven track record in discovering new drugs (and other molecules), it also has major constraints. In particular it has modest throughput and some practical diversity limitations – most theoretically possible small molecules contain structural elements that make them too time-consuming for a synthetic chemist to attempt – despite the fact that these “difficult” elements often confer important pharmaceutical benefits such as activity and specificity. Partly as a consequence pharmaceutical compounds are often of limited originality.

However, organic synthesis is not the only way to make compounds, and one only has to contemplate those compounds that are found in or derived from nature (the statins, taxol, morphine etc.) to realise that compounds with exquisite design can be made by biological processes (as the result of a cascade of enzymatic reactions) rather than in the fume hood.

Indeed historically nature has been the single most productive source for novel drugs and this importance has continued into recent years. A recent review¹ lists c. 1,000 new chemical entities reaching market over the last 25 years of which c. 50% are natural, nature derived or inspired by a natural scaffold.

(¹Newman DJ, Cragg GM: Natural products as sources of new drugs over the last 25 years. J Nat Prod 2007, 70:461–477.)

However classic natural product approaches have become increasingly difficult as the small percentage of natural organisms that are easy to harvest (large plants, culturable micro-organisms etc.) have been “mined out”. As a consequence the area has fallen out of fashion with the pharmaceutical industry and this immensely valuable chemistry space has been left more or less vacant.

Fortunately advances in molecular biology now allow completely new approaches to such biosynthetic compounds to be considered. Just as advances in genetics in the 1980s paved the way for single gene biologic drugs (which both replaced and greatly improved on traditional approaches of extracting material from pigs, cadavers, urine etc), so the further development of genetics in the 1990s now allows it to be used to make multi-gene drugs (i.e. small molecules) with potentially the same benefits.

These new tools also make it possible to explore unnatural biosynthetic chemistry. Despite the huge diversity of the modern natural world, it itself only represents a subset of those compounds that can or have been created by biosynthetic processes. Artificial biosynthetic (or genetic) chemistry can both create compounds that have never been made in nature or that (literally) went out with the dinosaurs.

Overall Concept 2 – Optimisation by Selection

Evolution as a process is so associated with nature that it is often referred to as natural selection.

However evolution is a much more fundamental process – it is an emergent mathematical property of any set of self-replicating, somewhat varying, patterns. If a given variation makes a pattern more able to replicate than patterns not containing that variation (i.e there is a selection pressure) then patterns containing that element will come (over a series of replication cycles) to dominate the population.

Thus natural selection is just one subset of the universe of evolutionary systems. And indeed the use of “evolving” computer code (so called “genetic algorithims”) is commonplace in financial market modelling, image recognition and the design of engineering systems. In many respects the entire capitalist system can be seen as an evolutionary based ecology. Whilst biotechnology companies such as Maxygen have pioneered evolutionary principles to protein optimisation.

Evolutionary principles can also be applied to optimising small molecule compounds. As with other evolutionary systems two fundamental requirements must be met – a source of inheritable variation and selection pressure.

• Inheritable variation. Small molecules are not directly coded in the gene sequence, but are the emergent consequence of interactions between different proteins (primarily enzymes). A given small molecule may be the direct consequence of 10 or more enzymatic steps, and indirectly affected by many more. So whilst with protein evolution it is sufficient to vary patterns within a given gene, to evolve small molecules you need to vary patterns across many different genes. This means you need the ability to combine large numbers of different genes.
• Selection Pressure. There must be a means to select for those gene combinations that give you a desired property (that confer “fitness” in evolutionary terminology). Fitness is an arbitrary, essentially mathematical definition – it may equal the length of a giraffe's neck, or it may equal the ability of a compound to activate the p53 tumour suppressor gene. It is ultimately, whatever the selection conditions say it is. Fortunately the pharmaceutical industry abounds with assays that can be used for measuring the fitness of a given combination, although such assays normally need adaptation to screen at the single cell level.

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