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Q&A with Biocatalytic Nitro Hydrogenations team

What was your role within the team?

Matthew Harris: I was an undergraduate summer internship student, working under guidance from existing Vincent group members to help investigate, at the time, a ‘thought experiment’ using existing Vincent group materials – nitroaromatic compound reduction by hydrogenase enzymes. Since then, I suppose, the rest is history.

Max Robertson: I started working on this catalyst system as a MChem research student and then continued on as Research Assistant. My role has been to investigate the selectivity of the catalytic nitro reduction and identify conditions to change the major product of the reaction and explore substrate scope for these new conditions.

Tara Lurshay: I conducted experimental work for my PhD (DPhil) with the Vincent group, primarily focused on the electrochemistry of the biocatalyst components and developing a predictive approach to substrate scoping, including extending this to aliphatic-type nitro substrates. I collaborated with HydRegen for continuous flow demonstrations, and now work full-time on commercialisation of the technology at HydRegen.

What were the biggest challenges in this project?

Matthew Harris: Projects challenges adapt over time. At the stage I was involved in the hydrogenase project, it was important to identify simple analytical techniques we could use to probe what, if anything, would happen to nitro compounds incubated with hydrogenases.

Max Robertson: On my side of the project, the biggest challenge was definitely the lab rearrangement after a roof leak, which was a surprisingly long and arduous process, but we are in a much more secure position now.

Sarah Cleary [worked as a Postdoc in the Vincent group during early demonstration of the technology, and now Chief Scientific Officer (CSO) at HydRegen]: There is so much possibility with this technology, part of the challenge is knowing where to focus in terms of chemical scope, exploring mechanistic aspects, and commercial prospects.

Rhiannon Evans [worked as a postdoc in the Vincent group on mechanistic studies of hydrogenases, and is now Head of Molecular Biology and Enzyme Production at HydRegen]: Hydrogenases are very large and complex molecules, they contain metals and have complicated maturation processes. The ability to get a high yield of these enzymes to enable low cost of goods is not a trivial challenge.

What different strengths did different people bring to the team?

Max Robertson: The diversity of the team is astonishing – we have incredibly talented people at all stages of the process, from the team at Harwell providing us with more pure and more concentrated enzyme, the electrochemists greatly helping with our understanding of the enzyme, the biotech group with an endless drive to improve our process and explore new avenues, and the HydRegen team focusing on industrial scale-up. It couldn’t have been done without everyone’s collaborative efforts.

Sarah Cleary: The discovery and exploratory work blended strengths in organic chemistry, biocatalysis, and electrochemistry. Development and commercialisation work continues to require those strengths and has brought on the need for more process chemistry skills. Our strengths in molecular biology and fermentation science have underpinned our ability to make cost improvements to the technology. And our strength with market awareness helps us focus on the best opportunities for commercializing the technology.

Kylie Vincent [Professor of Inorganic ¾ÅÖÝÓ°Ôº, University of Oxford]: I’ve always tried to recruit researchers to my team who bring a completely different skill-set to mine, and that is how we have been able to develop such a unique catalyst system. This builds on years of our mechanistic enzymology to understand hydrogenases, careful analytical chemistry and electrochemistry to probe the workings of the catalyst, application of organic chemistry methods to demonstrate applicability to a broad range of substrates and to establish product quality. And now the catalyst system has passed to HydRegen for commercially directed scale-up. This is all possible only because of a multi-skilled academic-industry team.

Why is this work so important and exciting?

Max Robertson: I am a big believer that enzymes are the way forward for how reactions will be handled in the future as the world aims to be more sustainable. I think this work shows real potential to make a difference for a reaction that traditionally uses stoichiometric reagents or rare metals. Our process is also very atom-efficient and doesn’t require high temperatures or pressures, which is convenient as well.

Where do you see the biggest impact of this technology/research being?

Max Robertson: I think that due to the selectivity of the reaction our research shows very good potential for scale up for production of drug precursors or other building blocks.

Rhiannon Evans: The biggest impact is in the ability of our technology to yield uncompromised products (high selectivity) with improved safety of such reactions (e.g. lowering pressures and temperatures required and displacing the use of toxic metal catalysts). Bio-based catalysts also offer the ability to switch out solvents for more ‘greener’ alternatives, e.g. water solvent or green organic co-solvents. Our hydrogenation technology requires no cofactors, no co-catalysts and no precious metals and the 100% atom-efficiency of hydrogen gas as reductant provides a more sustainable solution to hydrogenation reactions of industrial relevance.

How will this work be used in real life applications?

Max Robertson: The nitro reduction is a very common reaction in synthesis, and a huge percentage of pharmaceuticals or pharmaceutical precursors include an amine group. Making chemical building blocks at scale seems to be the most likely usage.

Rhiannon Evans: Our biocatalytic hydrogenation technology is applicable to hydrogenation reactions, which make up about 14% of all industrial chemical reactions. Our technology therefore has the potential to be used widely across many different sectors, e.g. pharmaceuticals, bulk chemicals, polymers, flavours and fragrances. A key point to make is that our technology can slot-in to existing hydrogenation infrastructure, so is easily adoptable by chemical plants.

How do you see this work developing over the next few years, and what is next for this technology/research?

Kylie Vincent: It is such a privilege to watch academic research being translated to industrial application. A really exciting step ahead will be seeing HydRegen take the nitro-reduction catalyst system into commercial chemical manufacturing processes. Within the University, we have loads of new ideas for how we’d like to apply hydrogenase enzymes in new ways, so there are lots of new developments in the pipeline...

What inspires or motivates your team?

Max Robertson: Within the biotech subgroup of the Vincent group, I think we’re all relatively ambitious and curious – we can see huge potential for a positive change and this project gives us an outlet where we can tweak and tinker and explore some really interesting new possibilities. Within our team, everyone is super supportive – we’re all cheering each other on!

What is the importance of collaboration in the chemical sciences?

Matthew Harris: Collaboration is an essential part of the chemical sciences. Projects can rarely be completed by a single individual: collaborators provide results that are otherwise not easily-obtainable; mentors and previous project members pass on key skills and information; and support staff provide an important, stable environment in which scientific challenges can be focused on. In the case of the hydrogenase-based nitro reduction project it's refreshing to see so many people make significant contributions down the line.

Max Robertson: Everything! Our work couldn’t be done without everyone who is working now and the work from before that we have built upon. It’s quite inspiring being part of a collective push forward.

Sofia Helin: Collaboration is essential to look at problems from a new perspective. I am lucky to be on the Interdisciplinary Bioscience Doctoral Training programme funded by BBSRC, which has allowed me to pursue a project between chemistry, flow processing and biotechnology. Working on this project has given me the opportunity to collaborate with labs overseas and learn to use state of the art flow chemistry equipment.

What does good research culture look like or mean to you?

Max Robertson: Like most things in life, treat others how you would like to be treated. Being fair, kind, and collaborative, while holding my own research to rigorous standards and recognising others’ fantastic achievements has worked fairly well so far for me.

Kylie Vincent: Some of the most important aspects of research culture are curiosity, and confidence to have a go. I try to foster a creative, ‘can-do’ approach in the team so that everyone is empowered to find ways around challenges. Positive research culture also demands respect for differences and celebration of diverse backgrounds and ways of thinking.

How can scientists try to improve the environmental sustainability of research? Can you give us any examples from your own experience or context?

Max Robertson: As we’re working with enzymes, it’s very easy for us to assume that everything we do is more green than other processes, but I think there’s a real awareness in the group about saving resources and energy – high fume hood sashes and extra pipette tips add up, you can never be too vigilant!

Sofia Helin:  Something that was new to me joining the group after experience in a pilot plant was reducing the scale of experiments to improve sustainability. Not only can this improve efficiency when using precious biological samples, but it also makes for good chemistry. For example, we use an Octo reactor which allows for eight repeats in one vessel with identical temperature and stirring conditions, and trialling multiple substrates in flow maximises the use of a given quantity of enzyme. Sustainability in the lab is also important, which is why we are a bronze LEAF accredited lab and have worked to implement green usage policies for equipment and efficient freezer usage.

Tara Lurshay: This catalyst enables greener chemical synthesis and is suitable for use across a wide scope of compounds, including fine chemical and pharmaceutical targets where selectivity is especially important. Reduced waste and energy requirements for the process, enable the switch from limited precious metals to a bio-alternative catalyst within the same infrastructure, aligning with growing demand for more sustainable chemical processes.

What advice would you give to a young person considering a career in the chemical sciences?

Matthew Harris: Start small, start somewhere and keep talking to people. There's always more to learn.

Max Robertson: 23 is still young, right? What’s worked for me so far has been to focus on what I enjoy – I love solving puzzles and it’s easy to look over when things don’t go to plan if I celebrate properly when things go right! Other than that, make sure to take time off properly – you can always start again on Monday, if you don’t take the time to relax, you’ll burn yourself out very quickly.

Sofia Helin: My advice would be research what you are passionate about. In ¾ÅÖÝÓ°Ôº World you can find so many links to chemistry all around us. For example, I enjoy cooking and there is a lot of chemistry in the pickling, fermenting and reservation processes. A career in the chemical sciences is exciting because you can solve problems and make brand new discoveries, if you are a curious person, I would definitely recommend it!