Does spaghetti have anything to do with biophysics? Not at first glance. But, when Professor Stephan Nußberger of the University of Stuttgart explains his highly-complex research, pasta becomes a highly illuminating didactic tool. A look at the mysterious world of organelles and proteins.
Professor Stephan Nußberger, Head of the University of Stuttgart's Institute of Biomaterials and Biomolecular Systems (BIO), is one of those passionate scientists, and conducts research into natural processes in what initially appears to the initiated as an inaccessible dimension. But because Nußberger talks about and explains it in such captivating terms, one leaves his office after a few hours with the feeling of having peered into a fascinating universe. It's all about translocases, i.e., certain proteins that permit molecular chains to pass through cell walls.
And this is crucial to human life for one of the fundamental requirements for the functioning organism is that proteins, for example, arrive within the mitochondria, i.e., the “the power stations” found in every cell of our bodies, in the correct numbers and at the right time. Over 1400 different protein polymers need to be threaded through these pores into the human mitochondria. Any disruption to this never ending transfer results in serious illnesses. Of course, this knowledge is based on thoroughgoing fundamental research: the American biochemist, Günter Blobel, won the 1999 Nobel Prize for Medicine for his discovery of the fact that every one of a cell's organelles requires pores as well as specific receptors to be able to thread proteins through. It is also clear that proteins succeed in getting through the cell membrane countless times in every moment of our lives. But – how?
The science magazine Nature once described the process as “the art of sucking spaghetti”, says Nußberger, dishing up an extremely pithy image. The idea of slurping up long, sauce-covered noodles with gusto immediately conjures up a mental picture, at least among pasta-fans. Yet, who or, rather what is pulling the protein chains in? “How nature manages this is still not understood”, says the biophysicist and adds: “but that's why I’m here! As a physicist, it's all about the scientific challenge of finding that out!”.
Diving down to unimaginable dimensions
To give an idea of why it is so difficult to observe molecules or polymers as they transgress the cell membrane, Nußberger uses another analogy. The sun, he says, is about 150 million kilometers away from earth. One needs to imagine a similarly immense distance between us and the scale of a few atoms, because this is the dimension at which the activities of the translocases play out. Even with the hugely powerful microscopes available to the biophysicists in Nußberger's department, it is still extremely difficult to observe proteins in motion the way one might, for example, observe a worm burrowing into the soil. However, the Stuttgart-based researchers have managed to do something else which Professor Nußberger described in a noteworthy article, co-authored with Professor Werner Kühlbrandt of the Max-Planck Institute of Biophysics in Frankfurt am Main, which was published in the respected journal Cell.
In the summer of 2017, the two biophysicists in Stuttgart and Frankfurt succeed in creating a translocase with a resolution of 6.8 ångströms, whereby one ångström equates to about the size of an atom. In the image that Nußberger presents, one can see the structure of the translocase as well as its two openings, each with a diameter of elven ångströms, which bears a slight resemblance to a Viennese mask. As the professor says, he had already discovered ten years ago that mitochondrial translocases of this type – a TOM-translocase or “translocase of the outer mitochondrial membrane” to use the correct technical jargon – have two pores. However, the fact that this finding is now available as a three-dimensional image with a resolution of almost atomic dimensions is, as Nußberger puts it with charming understatement “an elegant scientific result”.
Stubbornness and routine laboratory work
This result was achieved via routine, tangible work in the laboratory, where the scientists cultivated bread mold in 100-liter tanks, from which highly purified mitochondria as well as, ultimately TOM was isolated in a multi-stage process, which was then observed using Cryo-Electron Microscopy (Cryo-EM) technology, which won the 2017 Nobel Prize for chemistry. “What's fascinating about our work is that we are penetrating down to dimensions that no one has ever seen before us”, says Nußberger, explaining that his team is searching for structures whose appearance they don't even know. “But I’m also glad that it is possible to pursue this stubborn desire to understand fundamental biological questions in our academic landscape”, the scientist adds.
The open questions include such things as the actual mechanics of the “slip through”, i.e., whether the protein-spaghetti is pushed through or pulled in. At the same time, the biophysicist’s work absolutely provides the basis for practice-oriented applications. For example, initial efforts are already underway to use this type of nano pore for DNA sequencing. The findings from Nußberger’s department are also useful to cell biologists studying mitochondrial disorders.