Biotechnology scientist Nico Claassens: ‘Building a living cell is a bizarre challenge’

^{Text: Pauline van Schayck | Photo: Ruben Eshuis}

^{This article appeared in Wageningen World 2|2025, the magazine of Wageningen University & Research.}

Nico Claassens has spent his entire working life at Wageningen University & Research, except for a brief stint of two and a half years at the Max Planck Institute in Potsdam. He started at Wageningen 18 years ago as an Environmental Sciences student. After a Master’s in biotechnology, a PhD and post-doctoral research, he has spent the past five years putting together his own research team in the Microbiology chair group. They are working on designing new synthetic routes in bacteria.

In 2019, he was awarded a Veni grant, a personal grant in the Dutch Research Council Talent Programme. He wanted to get bacteria to grow on a substrate of molecules containing just one carbon atom. ‘Bacteria such as the well-known E. coli use sugars – with six carbon atoms – to grow and to make various substances. We utilize that fact in biotechnology to produce nutrients, medicines, biofuels and bioplastics. But if we can get the bacteria to grow on a diet of CO₂ – with one carbon atom – rather than sugars, we’ll be able to produce all those substances in a more environmentally friendly way, without CO₂ emissions. In my Veni project, we first tried using a different molecule with only one carbon atom, namely formic acid. It contains a small amount of energy and is easier for bacteria to use than CO₂. We then built the instructions for metabolizing this into E. coli by genetically modifying the bacterium.’

Did that work?

‘It did work, but the bacteria grew very slowly. The doubling time was eight hours, which is far too long for industrial production. E. coli has a doubling time of 20 minutes if you give the bacteria enough sugars and amino acids and make their life really cushy.

‘Suzan Yilmaz, one of my PhDs, discovered that one specific enzyme was very slow and the cell needed huge amounts of that enzyme. So we started a search for faster versions of that enzyme. We succeeded eventually by modifying five genes in the bacterium. We followed this with evolution to get the process to work even better. That let us get down to four hours instead of eight, which is much more acceptable for industry.’

You followed this with evolution?

‘Essentially, we let evolution do some of the work. We make major genetic changes to a bacterium, but it can’t cope with that very well to start with and doesn’t function optimally. Natural selection can then improve the bacteria. For example, we can give them formic acid only and any cells with a small, favourable mutation then grow faster and gradually take over the population. That process is fast enough in bacteria for us to make use of it. You don’t have to wait for months or years.’

In 2024, you were given a Vidi grant and an ERC Starting Grant for setting up your own research group. What did you do next?

‘We’d got it working with formic acid, so we started on converting CO₂. Almost all plants and bacteria that use photosynthesis to generate energy do so using a process that we call the Calvin cycle. Put briefly, this turns CO₂ into sugars. But that process uses energy, so we looked for different ways of converting CO₂. It turns out there are seven alternative processes in nature, one of which was discovered in Wageningen in 2020. But we are also trying to figure out for ourselves how a process to take up CO₂ might go. You could then use enzymes that have a different function in nature but that could still play a role in the process we have thought up.’

How do you test these processes in practice?

‘We use a different bacterium, a soil bacterium called Cupriavidus necator. It normally fixes CO₂ via the Calvin cycle, but we were able to build in an alternative to the Calvin cycle through a lot of genetic modification plus some evolution. Then the bacterium suddenly started growing better and producing more. That was great evidence supporting the idea that the Calvin cycle can be circumvented.’

Why isn’t there something like that in nature?

‘That’s because of how evolution works, namely in small steps that improve a process. A completely new process is a very big step. Of course that’s possible too, but it is far less likely. That is why the Calvin cycle is found in so many places on Earth, in so many plant species and in some bacteria. Alternative processes have only developed in certain bacteria that live in unusual places such as in the depths of the ocean where there is hardly any oxygen – in other words, in extreme conditions. We simulate extreme conditions such as 10 per cent CO₂ in the lab too; in nature, that figure is 0.04 per cent. Our bacteria probably wouldn’t survive outside the reactor where they are kept now.’

So your bacteria live in a reactor where the main input is CO₂. What is the output?

‘Bacterial cells produce all kinds of basic molecules for their metabolism, for example alcohol, acetic acid and various proteins. Those also end up in the medium that the bacteria are growing in. If you extract these molecules, you have the building blocks for making a wide range of other substances.

‘There are also interesting substances inside the cell. The Cupriavidus bacterium, for example, makes little pieces of plastic; you can see them under the microscope. To extract that material, you first need to break open the cell. Extracting the products from the medium or the cells requires a lot of energy, which is why you need a high concentration to make it worthwhile for industry.’

What do you eventually hope to be able to produce on an industrial scale?

‘We are working on replacing animal proteins, for example by using bacteria to produce the milk protein casein. If we’re successful, fewer farm animals will be needed. That would bring substantial benefits in terms of lower emissions of CO₂, methane and nitrogen compounds and less deforestation. But it’s extremely difficult to get bacteria to produce milk proteins and then use the proteins to make cheese.’

You are also working on bioplastics?

‘Yes, I have high expectations there. Bacteria were already being used to produce bioplastics back in the 1980s, but that often turned out not to be economically viable. Also, there is more of a focus on sustainability and ending our reliance on fossil fuels now than there was in the 1980s. On top of that, these days we have new genetic techniques such as sequencing that let us determine the DNA code. That makes this research much faster and cheaper.’

You are also closely involved in a major Dutch project that aims to build a living cell. Why would you want to do that?

‘I agree it’s a bizarre challenge, but we are incredibly curious to see whether it’s possible. I don’t know whether we will achieve this in the next ten years, but we will learn a lot from this endeavour. For example, someone in the consortium will discover something new and we’ll be able to use that for our research into converting CO₂. That’s why we’re doing it.’

‘That synthetic cell will consist of extremely simple biological modules, as simple as possible, such as components for copying DNA, making proteins and producing energy. So we’re trying to break down life into pieces, with each function as a separate component. Imagine you replace a complex process for producing the energy storage molecule ATP with a simpler process, maybe one that works better too. Then you use evolution to improve that process further and get a better understanding of how it works. Those modules eventually end up in the synthetic cell we’re building.’

How do you feel about the ethics of intervening so extensively in how a cell functions?

‘Of course people sometimes get a bit worried about what we are doing, but we are just using natural processes. People have been combining genetic properties in agriculture for a long time, but now we have the tools to do it faster and to understand what is happening better. What matters is what it’s used for. If a company used techniques developed in our research to be able to sell more pesticides, I would be opposed to that.’

You set ambitious goals in your research; as you say yourself, ‘bizarre challenges’. Where do you get your motivation?

‘My dream is to have such a thorough understanding of biology that we can say we need this bacterium to make that product, order the genes we need, insert them in the bacterium and get something that works. I’m optimistic we will achieve that one day. To get there, sometimes you simply need to give ambitious ideas a try and not give up too easily. I’ve seen a PhD candidate toil away for two years trying to get a bacterium to grow on methanol. He kept looking more and more downcast because nothing worked. But he went on holiday and when he came back, one test tube of his culture was completely full of bacteria. A chance mutation had arisen and the bacteria were then able to grow on methanol after all. Those are nice results. Sometimes you need perseverance combined with a dash of luck to achieve a breakthrough in your research.’