Alcohol prevents destruction

In the Netherlands alone, people drink approximately 1.1 billion litres of beer every year. Beer, the first alcoholic beverage, was invented approximately five thousand years ago. It’s still the most popular drink in the world.

But RUG systems biologist Matthias Heinemann says we are lucky that Leffe Blond, Grolsch, and Kilkenny exist at all. They wouldn’t if it weren’t for a little-known mechanism in the yeast cell: a kind of safety valve. Heinemann discovered how this valve works and published his findings in the prestigious journal Nature Metabolism.

Beer brewing

‘It actually doesn’t make any sense for yeast cells to produce ethanol’, Heinemann explains. The yeast cell Saccharomyces cerevisiae, used to brew beer, ferments the sugar in malt by breaking down glucose into ethanol.

So the yeast cell leaves part of its energy unused

But it would do better to turn the glucose into carbon dioxide. The yeast cell takes a molecule made up of six carbon atoms (glucose) and turns it into a molecule made up of only two of those, turning it into ethanol. But carbon dioxide has only one carbon atom. ‘So the yeast cell leaves part of its energy unused’, says Heinemann.

This would make sense if there is no oxygen available, like during the beer brewing process. It can’t make carbon dioxide without oxygen atoms. But yeast turns the glucose into ethanol even when there is oxygen available.

Heinemann thinks that’s amazing, and so do many other scientists. One would expect that evolution would have done away with this inefficient use of energy. ‘But it hasn’t.’

Strange behaviour

Other cells also exhibit this strange behaviour. The E. coli bacterium that lives in your bowels and helps you digest food produces acetate instead of alcohol. E. coli doesn’t fully break down glucose, either. And cancer cells produce lactate, which is another product of insufficiently broken down glucose.

Maybe there is a story to tell about all of this, Heinemann thought. ‘If all these organisms behave the same, maybe I should look for the answer to that behaviour somewhere else: in how the cell itself works.’

It’s been eight years since Heinemann asked himself this question. Around that same time, he received an e-mail from the RUG asking if he was interested in working in Groningen. Because he’s not just a systems biologist: ‘I trained as an engineer’, he says. ‘After that, I did a post doc and became a biologist. But I’m still really technical in my approach to things.’

Gut feeling

The RUG offered Heinemann a ‘very good package’ to continue his research here, he says. ‘They gave me funding for PhD students without me having to write so much as a proposal. That’s the only reason I’m even able to do this research.’

And so Heinemann left Zurich for Groningen to start a study that had no guarantee of succeeding. He says he just had a gut feeling that the answer to the ethanol problem might turn out to be very important.

I was just at a complete loss sometimes

He decided to approach the yeast cell as though it was a machine. First he created a model for the approximately thousand different chemical reactions taking place in a cell. Then he added thermodynamics.

Computing power

‘I looked at the speed with which the cell releases Gibbs energy’, he explains, which is released during a chemical reaction. He suspected that there was a limit; a maximum speed at which the cell reactions are able to release this Gibbs energy.

Figuring this out wasn’t easy. He worked alongside his PhD students, Bastian Niebel and Simon Leupold, creating endless computational models. These required the computing power of the CIT; there are thousands of reactions in a cell and millions of possible outcomes.

After three years of their research, the team had nothing. ‘I was just at a complete loss sometimes’, Heinemann confesses. ‘When one of my PhD students had no results and nothing published after three years I couldn’t help but wonder if the research was worth continuing.’

Sense

But they stuck with it. And in the end, it paid off.

When more glucose is introduced into the yeast cell, the cell releases more Gibbs energy. But that energy isn’t limitless. When it reaches the limit, ‘that’s when the cell starts producing ethanol’, says Heinemann. The same goes for the E. coli bacterium: the cell hits the energy limit, and then it secretes acetate.

Honestly, I’m surprised no one else tested this process before

In other words, the cell has a kind of safety valve that prevents it from fully breaking down the glucose, which limits the energy that is released. Too much energy would damage the cell itself.

Now that he’s got it all down on paper, it makes a lot of sense, he says. ‘Honestly, I’m surprised no one else tested this process before.’ As his results became more reliable and his research neared its end, he became increasingly fearful that a competitor would publish on the topic before him. ‘I couldn’t believe that no one else had figured this out.’

Chaos

Since then, he’s already made other advancements. Now that he’s proved the principle of the safety valve, Heinemann wants to know what takes place in the yeast cells that requires this valve in the first place.

He’s looking at movements within the cell itself. ‘What if part of the energy that’s released during a reaction actually displaces the protein, causing another reaction?’ he says. ‘Like a little push, almost. If it’s just one reaction, that’s not that big of a deal. But if it leads to too many reactions, that might lead to chaos within the cell. It might even prevent the cell from functioning.’

It’s just a hypothesis so far, but his gut says it’s a good one. He is currently working on a proposal to get a grant from the Dutch National Research Agenda so he can test it.

Explaining a fundamental mechanism within cells could have many implications. Yeast cells are very important for manufacturing various chemical substances. Potentially, the pharmaceutical industry could also use the knowledge gained to destroy cancer cells. ‘If you know the valve releases energy to stop the cell from being destroyed, why not close it off and see what happens?’

Dutch