At the heart of the central dogma of biology — that DNA makes RNA and RNA makes proteins — is the ribosome. Ribosomes serve as a cell’s protein factories, linking amino acids together into complex proteins according to instructions encoded in the cell’s messenger RNAs. It’s a process that is repeated millions of times a day in every cell and is critical to all life.
Sebastian Klinge, Rockefeller’s newest tenure-track faculty member, has dedicated his career to understanding the ribosome, with a particular emphasis on its atomic structure and the process by which it forms in the cell. Klinge was appointed assistant professor in June and will open his lab, to be called The Laboratory of Protein and Nucleic Acid Chemistry, on September 15. He is the first faculty member to be recruited under the university’s nine-year strategic plan approved in 2012.
The ribosome’s workings have been the subject of intensive study since it was first identified half a century ago. “But despite all the attention it has received, relatively little is known about the process by which it is assembled from dozens of molecular subunits,” Klinge says. “My laboratory will focus on understanding how the synthesis of the eukaryotic ribosome is achieved at an atomic level.”
A native of Hanover, Germany, Klinge was drawn to biochemistry in his teenage years. He attended both undergraduate and graduate school at the University of Cambridge, receiving a B.A. in biochemistry in 2005 and a Ph.D., also in biochemistry, in 2009. He has since been a postdoc at ETH Zurich in Switzerland.
Ribosomes were discovered at Rockefeller, by George Palade and his colleagues, in the 1950s. The university has a long tradition of cellular biology, as well as structural biology and biochemistry. All three will be important to understanding the basis of ribosome assembly. Although scientists have a general understanding of the structure of the ribosome as a whole, the process of how it is put together from some 80 components by approximately 200 other proteins remains murky.
“You can think of the ribosome as a car,” says Klinge. “We have a pretty good understanding of how the car works and what the various pieces are for, but until you’ve gone inside the factory and examined the assembly line, you won’t understand how it is put together. What I want to do is study the raw materials, the robots doing the welding and the tools being used.”
The robots, in the case of ribosomes, are giant macromolecular assemblies made up of strings of amino acids. Because of their size and complexity, and their dynamic nature, macromolecular assemblies are notoriously difficult to study.
What’s more, it’s something of a chicken-and-egg problem. “You need the machinery to be in place in order to manufacture proteins, but the machinery itself is made of proteins that must be manufactured,” Klinge says.
But this will not be Klinge’s first encounter with large molecular components. As a graduate student, he studied a macromolecular assembly involved in the copying of DNA, the DNA polymerase alpha/primase complex, which helps initiate DNA replication by creating a “primer” molecule made of both RNA and DNA. And after moving to the ETH Zurich he shifted his focus to protein synthesis, determining the crystal structure of the large ribosomal subunit of the ribosome, the 60S subunit.
Klinge aims to elucidate not only the structural anatomy of ribosomal subcomponents, but also the biochemistry of the assembly process itself. Because the ribosome plays such a critical role in life, understanding how ribosomes “mature” has the potential to unlock biological secrets that are relevant to studies of genetics and gene regulation.
“We are delighted to welcome Sebastian to Rockefeller, where he will join a long tradition of research on the structure and workings of cells,” says Marc Tessier-Lavigne, the university’s president. “Sebastian’s research on ribosomal assembly sets out to answer important fundamental questions about the basic processes of life, and his record as a student and postdoc suggests he will take a rigorous and tenacious approach to his work. We look forward to seeing great things from him as he establishes his own laboratory.”