Professor Erich Wanker finds biology humbling – to see how proteins are created in cells and how they bind together to form units that distinguish a human from a vinegar fly. One cell can contain hundreds of thousands of proteins. These join together to form thousands of protein complexes, each with its own range of functions.
“Proteins are the most fascinating molecules that life has produced – they are unrivalled in their diversity and complexity,” says Professor Wanker, head of the Proteomics and Molecular Mechanisms of Neurodegenerative Diseases Lab at the Max Delbrück Center for Molecular Medicine (MDC). “In this network, even tiny glitches can result in hundreds of diseases.” He is researching how exactly these tiny glitches occur in the brain – or more precisely: how misfolded proteins and protein complexes prevent neurons from doing their jobs properly and trigger neurodegenerative diseases.
Wanker is particularly interested in Huntington’s disease – a condition that is currently incurable. Those affected live a normal life for decades, until neurons start dying off in certain areas of the brain. This causes patients to slowly and steadily lose control of their own bodies, muscles and thoughts – and ultimately results in their death.
“If we understand proteins and how they interact, we will be able to understand life and develop new therapies for many diseases,” says Wanker. He is a man who likes clear statements and big goals. But when he says sentences like this, they don’t come across as boastful; instead, you know they have a footnote attached to them that lists meticulously obtained findings from countless laboratory hours, experiments and studies. “In the future, we will be able to thoroughly understand cellular processes at the molecular level through improved biological analysis techniques, automation and computing power.”
Diseased fly brains
Wanker opens the door to a laboratory. His colleague Dr. Anne Ast is in the middle of setting up an experiment using Drosophila melanogaster, more commonly known as vinegar flies. The flies are buzzing around in a glass flask, but start to fall to the bottom as Ast puts them to sleep with carbon dioxide. She places the passed-out flies under a light microscope. Through the eyepiece, their bright red eyes are clearly visible. The researchers have introduced a mutated human huntingtin gene into the flies, which triggers Huntington’s disease by producing misfolded HTT proteins. “Using our fly models, we can measure how the altered huntingtin proteins clump together into aggregates and how this affects the neurons,” says Wanker. The researchers can also test which other proteins or protein complexes influence these deposits – and how it may be possible to slow the process down.
Wanker’s team already discovered that the aggregates can self-propagate by “handing over” a template of their own structure to healthy molecules – a process known as seeding. Ast and her colleagues have now detected precursors of the huntingtin aggregates long before the death of the first neurons has occurred. “The common theory up to now has been that aggregates form as a result of the disease,” says Wanker. “But in fact, they appear to be one of the early modifications that drive the disease.” These findings could improve diagnostics by, for example, helping to predict when the inherited disease will develop or how severe its course will be. They could also serve as a target for halting its progression at an early stage.
Delving into different worlds
If we watched a sped-up replay of Wanker’s life as a researcher, the first scene would be him as a student at the Graz University of Technology, full of enthusiasm about molecules. It would then cut to him as a graduate in technical chemistry, who is suddenly more interested in the processes of life than in technical procedures. This is when he dives head first into the chemistry of life – in the next shot we see him characterizing a bacterial enzyme, which he studies further in his doctoral thesis to find out whether it could be used to extract fructose from crops. In the following scene, he is in a white coat as a postdoc at the University of California in Los Angeles, analyzing cell samples under an electron microscope; he is now studying protein transport and secretion, and learning cell biology from scratch.
Cut to 1995 and we’re at the Max Planck Institute for Molecular Genetics in Berlin-Dahlem: Wanker has once again stumbled upon a new world – that of neurodegeneration. Two years earlier, scientists discovered the mutation in the huntingtin gene that causes Huntington’s disease. Now, as head of his own research group, he wants to shed light on exactly how the faulty huntingtin gene disrupts cellular function. “I saw it as my mission to apply all my knowledge of biochemistry and cell biology to answering this question,” says Wanker.
A far too lengthy chain
This was the start of a very intensive period. Wanker immersed himself in his work – sometimes barely leaving the lab for days at a time – and, in 1997, discovered polyglutamine aggregation. It seems the cell stutters when copying the huntingtin gene, causing three specific DNA bases to repeat at this site at a much higher frequency than normal. As a result, too many glutamine building blocks are inserted into the amino acid sequence of the huntingtin protein. Ultimately, as Wanker demonstrates, this glitch creates long polyglutamine chains that clump together to form the infamous deposits and “poison” the neurons. Polyglutamine aggregation research is now becoming a research field in its own right. If you search the PubMed database, you will find 2,000 studies on this – 65 of which include Wanker’s name. But it is still not known exactly how the elongated sequence triggers the disease. And that is something that Wanker also intends to find out.
“My desire to really lose myself in a topic comes from within,” explains Wanker. “I come up with ideas that excite me, and then I dive in and try get to the bottom of this world that I’ve created.” And he is the same in his free time with his passion for reading – soaking up the richly detailed language of Marcel Proust, the doctor’s son, or of Robert Musil, Joseph Roth and Thomas Mann. He was the same, too, as a child in Carinthia, Austria, where he would lose himself in the nature that surrounded his grandparents’ farmhouse – enchanted by the mysteries contained in every tiny stone, every insect, every flower. Or later at school, when he discovered the previously invisible world of molecules.
The search for a therapeutic molecule
When Wanker came to MDC in 2001, he became fully hooked on the world of proteins and their complex relationships – suspecting this is where he would find the answers to his biggest questions. He established the first MDC lab to ever address systems biology questions and used genetic methods to measure protein interactions. The yeast-2-hybrid (Y2H) method, which Wanker successfully automated, allows specific proteins to be introduced into yeast cells and detects their interactions. A robotic system runs millions of these experiments. Based on the data it produced, Wanker’s team published an interaction network in 2008 that contained 3,200 interactions between 1,700 human proteins. But this is a milestone he has long since surpassed: In 2020, he traced a web of 30,000 connections between 5,000 proteins associated with neurodegeneration. “Now we just have to figure out which ones are biologically relevant,” says Wanker wryly.
A new method now also exists that goes one step further. The robot test system LuTHy – affectionately dubbed Lucy by Wanker’s team – can measure with extreme precision how strong the binding is between proteins in mammalian cells. Furthermore, LuTHy can determine the distance between proteins in a cell. This is extremely useful information, as even the smallest shifts – such as those caused by mutations – can have major biological consequences and provide potential avenues for drug development.
Although Wanker says he sees himself as a “hardcore basic researcher,” knowledge of molecular processes provides valuable clues for developing therapies. His hope is to find a therapeutic molecule that can prevent the seeding process in Huntington’s disease – the conversion of healthy proteins into diseased ones. To do so will require him to delve even deeper, isolating aggregates from brain tissue samples and using methods he has developed himself to see if promising agents can be found – thus adding a new, meticulously compiled footnote to his grand vision.
Text: Mirco Lomot