Single-celled microorganisms that we have known for centuries. What could be left to investigate? A great deal, as it turns out.

The year is 1836. Charles Darwin is on his way back to England on HMS Beagle. Slurping from a glass of beer, he ponders one of the last holes in his nascent theory: how can gradual change be reconciled with new properties that seem to come from nowhere? Well, the scientist literally had the answer in his hands. 

Based on research with brewer's yeast, Saccharomyces cerevisiae, researchers from the VIB-KU Leuven Center for Microbiology discovered the principle of genetic tandem repetitions almost two centuries later - pieces of DNA that are repeated head-to-tail. While these can cause neurodegenerative disorders such as Huntington's disease and Alzheimer's disease, they also have a positive role in allowing cells to adapt to their environment more quickly. Rapid evolution, so to speak. 

"It used to be thought that a large part of our DNA was useless. That 'Junk DNA' was supposed to have found its way into our genome by accident", explains Professor Verstrepen. "But thanks to recent insights into genetics, we now know better. One example is what we call tandem repeats: pieces of DNA repeated several times in succession. Cells have trouble copying and transmitting these repetitions correctly. They sometimes add pieces of DNA or remove some of the repeats. Therefore, the copy often differs from the original, affecting the activity of the gene or even neighboring genes. For example, we showed that these unstable tandem repeats can be useful in some cases by allowing certain traits to evolve quickly so that the organism can adapt to a changing environment."

It is no coincidence that the theory was supported by yeast research. Yeast cells have nuclei and are eukaryotes, just like human cells. That is why they are known as one of the best genetic model organisms. What's more, they are easy to manipulate and reproduce at lightning speed – every two hours if they feel good. That makes them invaluable for, amongst other things, medical research.
 

Incidentally, Charles Darwin can be forgiven for not knowing that tandem repeats are an acceleration mechanism for evolution. The knowledge that DNA carried genetic information was far in the future, and the role of yeast cells in fermentation had not yet been described. Louis Pasteur, a contemporary and a pioneer in the field of microorganism applications, only discovered that the dregs of beer consisted of yeast cells in the middle of the 19th century. And it wasn't until 1883, a year after Darwin's death, that Emil Hansen of the Carlsberg Brewery first isolated yeast cells to work with.

Verstrepen: "In the meantime, we have been catching up. With the help of robotics and chip technology, we can do millions of experiments simultaneously on the cultivation and analysis of different types of yeast. It's going really fast now. And not only for fundamental scientific research. Yeast also plays a crucial role in the development of many industrial applications, from pharmaceuticals and bioplastics to food and drink."

Industrial yeasts differ greatly from the original wild-type yeast found in nature. This is because brewers chose ever more suitable yeasts and consistently reused them in subsequent brews to optimize certain properties such as taste and alcohol percentage. Since 2016 it has been possible to read how, where, and when this selective breeding took place in an actual beer yeast family tree, which starts with the original beer yeast found wild in nature. 

The complete genome was determined for 157 of these brewer's strains in the family tree. Based on this, an algorithm could determine which strains exhibit the same changes in DNA and should therefore be put next to each other on the tree. 

It is interesting to see, for example, that various subgroups of the family tree show that brewers have generally remained faithful to local yeasts. The yeasts of Belgian beers, for example, differ greatly from their British competitors.
 

"With genetic modification, it would become child's play. An efficient brewing process, a 100% predictable taste, and huge production volumes can all be done safely. But breweries shudder at the idea of 'artificial beer.' Consumers need to feel that their beer is crafted, so we reluctantly stay away from genetic engineering and stick to breeding. Nevertheless, we've seen signs of a turnaround in recent years. More and more people understand that genetic engineering can play a key role in a more sustainable, green, and efficient economy."

In 10 years, science made as much progress in breeding new, superior yeasts as farmers did in 10,000 years in raising livestock.

A new step followed in 2017. With the support of AB InBev and some 20 other industrial partners, Professor Verstrepen set up an experimental brewery in the KU Leuven's Arenberg Castle Park. The production capacity suddenly went from 10 to 500 liters. "This lets the team get closer to what happens in real breweries," Verstrepen continues. "Yeasts sometimes behave differently in large quantities to what we would expect from smaller volumes."

"The concrete questions we tackle in the brewery are of two sorts. On the one hand, we are working on the efficiency of the fermentation process. How can you shorten the brewing process? Or how can you save water by brewing lager beer with a higher alcohol concentration and then diluting it with water? On the other hand, we also look at the quality. For example, how do you make an alcohol-free beer that tastes good?"
 

A huge fridge full of beer sets off alarm bells in the average office, but here it is the most normal thing in the world.

In recent years, the team continued to work at a high pace. For example, they discovered that beers like Trappist owe their success to medieval superyeasts. Since September 2020, interested parties have also been able to follow an international postgraduate program in malting and brewing at the KU Leuven, where Verstrepen, together with other colleagues from the university and experts from AB InBev, explain the science and technology behind beer brewing. There was even a free online course on beer technology, which has already attracted 20,000 students worldwide.

The beer sector's achievements may appeal most to the imagination, but the yeast experts are active in many more areas. One thing that stands out immediately when it concerns anything other than food and drink is that molecular engineering techniques are at the forefront. For example, there are projects on bioethanol and bioplastics in which genetic modification, genome editing, and synthetic biology are all fair game. 

Verstrepen: "Sometimes we design whole pieces of optimized DNA by chemical synthesis. That seems futuristic, but it will soon be routine. This way, we can introduce completely new biochemical reaction pathways into the yeast cells so that they start making valuable biochemical components, sometimes even growing on waste streams."

 "The possibilities are legion, from making biofuel production processes more sustainable and making tasty vegetarian food to replacing polluting petrochemicals with clean biotechnology. In short, yeasts will still play an important role in our quest for a greener future."

Yeasts will still play an important role in our quest for a greener future.

Fundamental research will also continue unabated. Among other things, the team is working on new molecular technologies to improve the genetic engineering of the yeasts further. 

"This dual mission – fundamental and applied research – has been our strength since the center was set up," concludes Verstrepen. "We don't actually make a strict division in this either. Sometimes we get ideas from brewers' practical questions, which lead us to fundamental genetic research. Conversely, this fundamental research also lets us offer broad expertise to the industry. For example, at the request of a brewery, we recently bred a yeast that can live longer. Of course, we now also want to find out what has just changed in the DNA of those yeasts, which in turn can lead to new insights into biology and physiology. With Duvel Moortgat, a private lender even invests in a research fund; the 'Brewing Science Serves Health Fund' specifically aims to link applied beer research and more fundamental work on health. We want to continue on that path. So our doors are open to anyone who wants to participate. With yeast as the star of the show, of course."