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    The search for natural catalysts

    Can enzymes be used to improve drug substance production? Thierry Schlama and his development team have been investigating this question for over eight years, as they want to use enzymes in drug substance production not only to save time and money but also to reduce massive amounts of waste. However, finding suitable enzymes that can act as catalysts and make drug production processes cleaner is like looking for the proverbial needle in a haystack.

    Text by Patrick Tschan, photos  by Laurids Jensen

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    View of Thierry Schlama’s new lab on the Campus in Basel, where the team is re-engineering enzymes.

    arrow-rightTrillions of possibilities
    arrow-rightSaving time
    arrow-rightReducing waste
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    Published on 12/10/2020

    Thierry Schlama, a Principal Fellow in the Biocatalysis team at Novartis, stands in the ancient tradition of what in German is known as a “Hefner.” For centuries, these yeast breeders had produced moldy catalysts for brewers and bakers to convert sugar into carbon dioxide and alcohol. Schlama also produces enzymes, but highly specialized ones that trigger and accelerate chemical processes in the production of medicines

    Enzymes are a special kind of protein and are among the essential building blocks of every living cell. Each enzyme consists of 300 to 400 amino acids and contains at least one nitrogen, carbon and oxygen atom. Each enzyme also folds into a characteristic “globular shape,” giving each one an individual appearance and function.

    Another characteristic is that each enzyme has a specific “lock” where other molecules can dock as if they had the right “key.” If the “key” fits the “lock,” enzymes catalyze chemical processes.

    One well-known example is the way yeast enzymes break down the sugar in bread dough into oxygen, making the bread airy. In beer brewing, the enzymes convert the starch in the mash into alcohol. As a result, the beer becomes alcoholic and carbonated.

    Although this process works so efficiently with yeast and sugar, it is extremely hard to find the right enzymes for the several hundred thousand known chemical syntheses used in industry. This is unfortunate, since catalysis with enzymes has considerable advantages for chemical processes. Compared to conventional catalysts, such as solvents and heavy metals, enzymes create almost no waste, need little energy and cost less. 

    In order to leverage the efficiency of so-called biocatalysis, Thierry Schlama and his team have set out to design specific “locks” on enzymes to match the “keys” of the molecules that are used in drug production processes. For this purpose, the amino acid sequences of the enzymes need to be changed.

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    State-of-the-art equipment used in the automatization of high-throughput sample preparation...

    Tril­li­ons of pos­si­bi­li­ties

    “Our task is to find and produce the right ‘locks’ to existing ‘keys’ that are suitable for our production processes among several thousands of enzyme variants,” is how Thierry Schlama describes the work of his team. “Enzymes are relatively flexible and have the ability to recognize the position of the key in the molecule where the reaction has to occur. They have the ability to cooperate with other enzymes. In that sense they are intelligent, and we can exploit their intelligence.”

    The process works like this: In a first screening, several hundred enzymes are scanned. If an enzyme is found in which promising conditions prevail for attaching a “lock” to the “key,” the engineering part begins, where the selected enzyme is modified in such a way that it can be used as a biocatalyst in a production process.  

    But the modification is anything but easy. “We can theoretically mutate every single position of an enzyme,” Schlama explains. In concrete terms this means modifying each of the 300 to 400 amino acids to create new variants with amino acid composition in which the enzyme “lock” matches the “key” of a molecule. 

    Given the fact that there are 20 different amino acids, the possibilities to modify the enzyme sequence are nearly infinite: For a 300-residue protein the number of possible sequences is 20300 – meaning there are trillions of trillions of trillions of possible combinations. It would be easier to count the stars in the universe by hand ...

    To compute such mind-numbing numbers, Schlama’s team uses cutting-edge bio-informatics software. Without such a tool, substantial progress would hardly be possible in a reasonable period of time.

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    Liquid Handling Robot used for pipetting of high-throughput enzymatic screening reactions.

    Sa­ving time

    That this computing-intensive search is worthwhile, however, was demonstrated by the team in 2017 after one of its modified enzymes helped speed up the production of a heart medication, halving the manufacturing process from eight to four production steps.

    “Our success was based exactly on the same method. No particular luck, and yes, we knew it would be a hard case. For a long time, all the enzymes tested showed no reactivity ... we really started from scratch,” Schlama explained the search for the needle in the haystack.  

    Spirits were obviously high when the “lock” and “key” finally matched. It was proof that the method, called “directed evolution,” works. And it revealed a huge potential for efficiency gains for the hundreds of chemical reaction types used in drug substance manufacturing at Novartis.

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    RapidFire high-throughput mass spectrometry system.

    Re­du­cing was­te

    Through synthesis, in general, chemists aim to produce a new, usually more complex substance from existing elements or simple starting compounds. For this purpose, much like yeast enzymes convert sugar into CO2 or alcohol, the starting elements have to be taken apart and reassembled. Depending on the desired final product, this process requires energy, a suitable pH value, solvents and, in classical chemistry, catalysts such as metals, including platinum, rhodium, palladium and ruthenium, among others. For example, in the catalytic converter for cars, carbon monoxide and unburnt hydrocarbons react with nitrogen oxide and oxygen to form carbon dioxide as well as nitrogen and water.

    While traditional catalysts are very effective, their use, however, has major disadvantages: considerable energy consumption, toxic waste due to solvents and heavy metals and high disposal costs. 

    “Biocatalysis using enzymes has clear advantages: Enzymes work in a temperature range of 30° to 50° Celsius. This reduces energy costs enormously, as creating extreme environments for conventional production processes is not necessary,” Schlama details.    

    Furthermore, the solvent in biocatalysis is not a chemical but simply water. The residual water containing the residual enzyme can be purified in conventional wastewater treatment plants. There, bacteria simply feed on the enzymes.    

    Due to the low temperature, the enzyme-driven production processes can also take place in any normal reactor. “There is no need to build a special reactor for the reactions. And the risk of fire and explosions is enormously reduced,” Schlama explains. “All this lowers costs at various stages of the entire production process and significantly reduces its CO2 emissions.”

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    Shaker farms, used to agitate dozens of 96-well plates in parallel for enzymatic assays.

    New tools

    Schlama expects the technology to gain more pace thanks also to a recent agreement with Codexis, a protein engineering firm. “Thanks to our collaboration with Codexis in May 2019, we have obtained a highly efficient technology that will make the search for suitable enzymes more precise and faster,” Schlama says.    

    The deal with Codexis facilitates the development of enzymes, as Schlama and his team can now carry out all the work steps in Basel and design them according to their requirements.    

    “We are currently evaluating and testing the use of the enzymes from our enzyme collection in 120 to 130 production processes. About 20 percent of these trials show promising approaches, so that we have been able to develop them further,” says Schlama.    

    While the process could revolutionize the production of medicines, progress will not be as fast since all existing drugs whose manufacturing processes are altered by the use of biocatalysis must pass through regulatory approval, which is often time-consuming.    

    At present, some of the pharmaceuticals involving biocatalytic production steps are still in the early development phase, while others are more advanced – most of them in the fields of oncology and general medicine. “In some projects we expect a reduction of around one-third in time, costs and waste, including CO2 emissions. It’s a great start, but there is certainly more to come,” says Schlama, cautiously looking ahead to the future possibilities of biocatalysis.

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