Elucidating structure with protein chemistry
It was not Ashwin Chari’s actual plan to become a scientist when he was at school. He was very active in sports, played handball in the Swiss youth team, and later wanted to study sports medicine. An injury and doubts about the long training period as an intern doctor made him think about alternatives. “Looking back, I see it as a fortunate coincidence,” the biochemist recounts. Chari grew up near Zurich, Switzerland, and studied biochemistry at the ETH there. In the interview, he speaks High German without a trace of dialect. “I sometimes make a joke of it: When we have visitors from Switzerland, I end the conversation by switching to Swiss German. Most people are distinctly surprised,” he says with a wink.
From Switzerland to Germany
Structural biology already fascinated him during his studies. For his diploma thesis he applied at the Paul Scherrer Institute, the largest research institute for natural and engineering sciences in Switzerland. At the Swiss Synchrotron Light Source, he wanted to delve deeper into methods of structure determination. That is where he, through a collaboration, met Utz Fischer. He followed the group leader first to the Max Planck Institute for Biochemistry in Martinsried and later to the University of Würzburg, where Chari earned his PhD. “That was a good decision which I do not regret to this day,” he sums up. After receiving his doctorate, he continued to work in Fischer's research group on several projects, which he later pursued as part of a project position funded by the German Research Foundation (DFG) at the MPI-BPC.
His successful collaboration with Holger Stark, head of the Department of Structural Dynamics at the institute, already began in Würzburg: “Cryo-electron microscopy seemed very promising to me at that time, and I was attracted to developing biochemical methods for this technique. I really appreciated the tremendous degree of freedom I had working with Holger,” Chari emphasizes. “You can be wrong, but when an unconventional approach works, the insights are much more far-reaching than if I had followed well-trodden paths.”
Molecular machines as a challenge
“Chemical processes are constantly taking place in our body's cells, catalyzed by specific proteins called enzymes. How these proteins do their work is largely determined by their spatial structure,” explains Chari. Many proteins are also organized in complexes or so-called molecular machines. “Therefore, you cannot separate the way proteins work from their structure and from their environment,” the research group leader adds. Several labs at the MPI-BPC work on such protein complexes: Marina Rodnina and her team study the cell’s protein factory, the ribosome. Reinhard Lührmann’s emeritus group focuses on the spliceosome, the cell’s molecular cutting table. And Patrick Cramer’s department studies RNA polymerases, which copy the genetic information.
“The proteasome and the fatty acid synthase, for short FAS, which Holger Stark and I have been studying in recent years, are also molecular machines,” reveals Chari. The proteasome is considered the cell’s garbage disposal unit: It degrades proteins that the cell no longer needs or that are defective. The FAS produces fatty acids, which serve not only as energy carriers for our body, but also as building material for membranes or cellular messenger substances. “My fascination with these molecular machines developed out of a methodological interest,” he reports. After all, how they function in the cell can only be elucidated if we succeed in purifying them in their native state. To do so is no easy feat. The molecular complexes can become very large and may consist of millions of atoms. Moreover, they are very fragile and can easily disintegrate. Last but not least, they are often in rapid motion as they perform their work.
Chari’s group is therefore creating tools that stabilize the complexes but do not restrict their movement so severely that the machines lose their function. This allows the Göttingen researchers to capture and reconstruct the machines’ various operating stages like a film sequence. Although the Max Planck researchers have to optimize these tools anew for each complex they want to study, basic patterns can be recognized with increasing experience.
In addition to protein biochemistry, Chari’s research group uses X-ray crystallography and cryo-electron microscopy. “We are primarily biochemists who also use biophysical and chemical methods,” states the group leader. His team, which consists of two postdoctoral researchers, three PhD students, and two technical assistants, is correspondingly multidisciplinary.
The researchers also want to use the innovative methods developed in the group to investigate new therapeutic approaches. Their motivation is that malfunctions of large cellular machines can cause various diseases in humans. Inhibitors for the proteasome, for example, increase the spectrum of therapeutic options for cancer. One focus of the group is to develop and incorporate chemical anchors into molecules that restrict their movement in specific areas. “Ideally, these chemical anchors can trigger or elimi- nate malfunctions of the molecular machines, revealing causes of disease. Perhaps this may lead to a new thera- peutic approach? We have learned in the past that it is important to be versatile, open to new ways of solving problems – and, above all, to persistently work on a solution,” emphasizes the biochemist.
When asked whether he had to learn this, he answers with a smile: “My wife would say I am stubborn. Already in school, I could puzzle over a math problem forever until I finally solved it.” Perhaps his past as an athlete also helps him: “As a handball player, I learned that talent is good, but it only takes you up to a certain level. Without hard work and persistence, you do not get to the top.” (is/cr)
Five questions to Ashwin Chari
What fascinates you most about your job?
When you start a project, there seem to be almost insur- mountable hurdles and you tread water for a long time. This often lasts until you eventually do the decisive experi- ment. Then, suddenly, everything seems to be coherent and simple. This moment of realization is by far the most fascinating experience.
How do you recharge your batteries after a tough day?
It varies: reading something non-scientific, or exercising a bit. Sometimes gardening helps, too.
What would you do if you had more time?
I like different languages. If I had more time I would learn other languages.
If you could choose freely – where would you live?
Although I grew up in Switzerland, I could well imagine living in a slightly warmer climate.
Where can one meet you in or around Göttingen on a day off?
On a short hike in the Göttingen countryside.