The production of pharmaceutical medicinal products is accompanied by large quantities of waste, as their synthesis requires numerous processing steps. Helma Wennemers, Professor of Organic Chemistry at ETH Zurich, works on reducing these steps by means of novel catalytic reactions, supported by a FET-Open Grant. She takes inspiration from nature’s systems: an interview with Professor Wennemers and her team.

Professor Wennemers, in the FET-Open Project CLASSY you are working together with your team on a new technology for which you use nature as your source of inspiration. How does it look like and which aspects of nature would you like to mimic?

Helma Wennemers: Nature is a great provider of ideas for natural scientists. Nature had millions of years to develop life and optimise its processes. We incorporate the principles of natural evolution into our project and use these fundamental concepts as tools to develop and optimise catalysts. Since catalytic processes are highly complex rational design alone is not yet sufficient, and maybe will never be, to develop an optimal system. We therefore use smart screening methods, procedures with which thousands, even millions of compounds can be tested, in order to identify the most suitable one. This process is similar to natural evolution and that we mimic at the laboratory scale.

You say that rational design alone is not enough. Are we dealing with science fiction then?

Let’s put it this way: we always have a clear objective. However, research means to advance into the unknown, you do not know what awaits you. We have a very distinct plan of where we want to go and a clear rational strategy of how we want to get there. This requires a solid education – in our case in molecular chemistry. But every challenging project has aspects that do not work as expected since not everything has yet been understood. Then you have to solve the previously unidentified problem or find a way to reach the objective by a different route. This is why research cannot be completely planned. And thus makes research extremely exciting, like a walk into a jungle that is yet to be discovered.

Since November 2019, you have been working on CLASSY with other research groups. Who is working on what?

Our team consists of six scientific groups. The coordinator is in Madrid, two groups are in Holland, one in Be’er Sheva, one in Graz, and we are in Zurich. Jointly, we use unconventional tools to develop novel catalysts and processes. We combine various areas of expertise that have not been brought together in the past: the groups in Spain and Israel work on self-replication. The Dutch teams are experts in microfluidic systems. They produce tiny droplets that serve as reaction vessels and, like compartments in our cells, control when their content comes together and reacts. The expertise of the group in Graz is biocatalysis, the use of enzymes, and we contribute our expertise with catalytically active peptides as well as in chemical biology and supramolecular chemistry.

Do you know some of the researchers from former cooperation projects?

I have known the colleagues from Graz and Nijmegen for a long time and I have been familiar with the work by the researchers from Spain and Israel. You know, in science we are one big global family. With Wolfgang Kroutil from Graz I collaborated 15 years ago within the scope of an EU Training Network. Already back then we discussed the idea of combining enzyme and peptide catalysis. However, the time had not yet been ripe back then. When the researchers from Spain, the Netherlands and Israel contacted me for the CLASSY Project, I brought the colleague from Graz to our team.

What do the individual process steps look like?

Together with the groups from Graz and Nijmegen we try to let enzymes act in concert with peptide catalysts. This is not trivial, since one cannot take for granted that they can co-exist, be compatible with each other, and act in synergy. In case single pot reactions would not work, we can – thanks to the expertise of Wilhelm Huck from Nijmegen – wrap the peptide into one droplet and the enzyme into another one, join the two droplets and trigger another reaction.

How do you manage physical collaboration in these times?

We were able to hold the kick-off meeting here in Zurich and get to know each other personally, including all of our PhD students and postdocs, which was very important! Due to the pandemic, all meetings thereafter were virtual. Fortunately, also the PhD students connected from the beginning and are now communicating bilaterally or trilaterally via Zoom.

Jasper Möhler, PhD student: Indeed, we hold meetings at regular intervals in order to discuss the greater goals, we divide the projects into smaller subprojects, some of them in the Netherlands, some of them in Switzerland. We exchange information about the results and also discuss details internally. I am delighted to see how well it works and how much one is able to achieve as a team of different research groups.

Wennemers: I am very proud to see how the team members are making this project their very own, how they come up with their own ideas and mature into leaders during the process.

You contribute to this project with your expertise in peptides. What do these particles do?

Peptide catalysis has been an important pillar of my group for a long time. In our research, we explore whether peptides can function as catalysts and, if so, how efficient they can be. At the beginning of this work, I was told by many experienced researchers: «This will not work! After all, nature has developed enzymes as catalysts and not peptides.» In nature as well as in our everyday life peptides, mini proteins if you wish, are omnipresent and serve, for example, as hormones and neurotransmitters. Also, many therapeutics are peptides. The sweetener aspartame is a peptide. However, there is not a single catalytically active peptide known in nature. Hence, our question is indeed unusual. It has substantial implications for today’s society but also for the understanding of the evolution of enzymes. And, after all, it is possible that peptides served at one point in the primordial soup as catalysts – a fundamental question, curiosity-driven basic research.

However, CLASSY distinguishes itself precisely by the fact that the project is very application-oriented.

Correct. If a peptide is an efficient catalyst, industry could, for example, use this peptide for the large-scale manufacturing of a drug.

Thereby, the production of medicines would generate less waste.

Exactly. This is the basic concept of catalysis. Catalysts enable the transformation of a molecule A into a molecule B and emerge unaltered from this reaction. If a single catalyst molecule converts millions of molecules A, the quantity of generated waste is significantly reduced.

Why has the problem of waste volume been neglected for so long? Is it that difficult?

That problem has been identified a long time ago. One of the first large catalytic processes is the Haber-Bosch synthesis of ammonia, which was developed by Fritz Haber and Carl Bosch at the beginning of the 20^th century. Catalysis is a central topic in the chemical industry and many catalytic processes are used. Now, we are bringing peptides into play.

And how far did you get by now?

We managed to develop a peptide that is capable of converting thousands of molecules A into molecules B. Our peptide catalyst is very robust and functions even in the presence of a multitude of so-called functional groups that are present in our bodies and many therapeutics. Here, Jasper achieved a truly remarkable advance and contributed the first publication within the CLASSY Project.

Jasper Möhler: This was not my achievement alone but rather built on previous works performed in our group. Now we are trying to trigger several reactions simultaneously with various catalytic systems in order to produce very complex products in a single reaction vessel.

Wennemers: And we are well on track. However, at present the enzymes are the limiting factor and not the peptides.

Group members have participated in ten symposia since the beginning of the study. How important is this presence for CLASSY?

During typical times, I would give 20 to 30 lectures a year at symposia and other universities and my group members discuss their research at conferences and with other scientists from around the world who visit us at ETH Zurich. This is part of the scientific exchange and is sorely missed during the pandemic – at all levels.

According to the department’s website you work in nine different fields of chemistry. Is this interdisciplinary approach a prerequisite to participate in projects such as CLASSY?

As a woman, you always have to work harder than men (she laughs). No, more seriously, every scientist has a different character. There are many excellent researchers who dedicate their life to one single topic. I personally enjoy diversity, as long as I can maintain excellence in different fields. In my lab, the seemingly highly diverse areas allow us to go beyond traditional boundaries, this is great.

What are the next steps in the project?

We are now at a stage where we establish and optimise synergies between peptides and enzymes for various systems. We aim at developing these cascade reactions further. In addition, we focus on combining metal catalysis with peptide catalysis. These could then be combined with enzymes and we would have all three pillars of catalysis in one pot: biocatalysis, metal catalysis and organocatalysis.

What are you most proud of in this project?

My group members!

Interview with Helma Wennemers (in German)