When Nenad Ban was an undergraduate at the University of Zagreb in Croatia, he set his eyes on a long-standing biological problem: He wanted to crack the atomic structure of the complex molecular assembly responsible for protein synthesis. It was a tall order: The first crystals of ribosomes--the cellular factories that translate nucleic acids into proteins--had been obtained in the early 1980s, but there were few labs with either the technical capacity or the desire to determine their structure. "It was clear that it would take quite a lot of efforts and ... not clear whether it would be really possible to be done," Ban says.

Yale University was one of the few places using x-ray crystallography to study the structure and function of such biological macromolecules. But Ban wasn't accepted into Yale's Ph.D. program, so he went to the University of California (UC), Riverside, where he complemented his biochemistry knowledge with skills in crystallography and computer science.

Four years later, with his Ph.D. and a dozen journal articles in hand, he found his way to Yale as a postdoc in the lab of molecular biophysicist Thomas Steitz. Steitz and Peter Moore, a biophysical chemist at Yale, had discussed using x-ray crystallography to solve the structure of the ribosome for years. "I was impressed not only by Nenad's energy and intelligence, but also by his willingness to consider such a high-risk, but high-reward project," Moore writes in an e-mail to Science Careers. "Most young scientists are more cautious than that, which explains why we needed someone like Nenad to get the project under way." In just 5 years, Ban had the structure dancing on his computer screen.

From vision to reality

If there is such a thing as a family predisposition to a scientific career, Ban had it. His father was a chemistry professor and his mother a biology professor at the University of Zagreb in their native country. "Between them, I heard a lot about chemistry and biology, and in the end decided to study molecular biology," Ban says. Yet, "I cannot say that ... this was the reason for my motivation." His original plan was to apply molecular biology to marine biology, but he soon developed a strong interest in the detailed structures of molecules. "Understanding structures of molecules gets at the core of their function, and in a way ... allows the most complete description of the biological processes they mediate," Ban says.

A research project on the biochemistry of protein synthesis during the final year of his B.Sc. degree prompted his desire to visualize the three-dimensional structure of ribosomes. After graduating in 1990, Ban went to the United States to do his Ph.D. at UC Riverside with crystallography expert Alexander McPherson. This meant leaving protein synthesis aside for a while, instead working on viruses and macromolecular immune complexes. But "I didn't mind," Ban says. "These were exciting projects and a fantastic way to get into crystallization and structure determination."

Once he moved to Yale for his postdoc in 1994, he felt he was in a position to take risks because he had published extensively while earning his Ph.D. "People who do well for their Ph.D. would be well-advised to tackle something that is a little bit more difficult," Ban says. "Nobody knows really whether it is going to work out, but it is worth a shot."

Ban chose to work on one of the most difficult problems in structural biology: imaging the active site of the ribosome, a site within the large subunit of the ribosome where the bonding of individual amino acids into a protein chain is catalyzed. "When he started working on the [large] subunit, ... a large and well-funded group in Germany that had first crystallized it had been working on it for years and made little progress on determining its structure. So for a postdoc to want to take this on at that stage was remarkable," Venki Ramakrishnan, a ribosome researcher at the MRC Laboratory of Molecular Biology in Cambridge, U.K., writes in an e-mail.

Parsing out crystallographic structures requires a lot of abstract computer calculations, "and these calculations can take years without you knowing ... whether you're moving in the right direction or not," Ban says. Ban approached it as if he were climbing a mountain without a map. On his way up, he secured what he calls "base camps," sets of calculations in which he had as much confidence as one can have. Should he go astray, he could return to these base camps and start out again, he says.

A turning point came a couple of years into the project, when Ban found that some calculations didn't make sense. "It took a lot of confidence to actually realize that things did not make sense, not because the problem was difficult but because the crystals had a specific type of ... 'pathology,' " called twinning, Ban says. The crystals had grown symmetrically, sharing parts of their skeleton. This new understanding allowed him to draw maps of the active site 2 years later.

Ban and Poul Nissen, a membrane protein researcher at the Aarhus University in Denmark who was also doing a postdoc in Steitz's lab at the time, pushed to determine the structure of the large subunit of the ribosome at high resolution. The day finally came when "we sat in front of the computer and ... really looked at this amazing structure after 5 years of efforts and lots of discussions," Ban recalls. "This moment of visualizing the active site of the ribosome is probably the most exciting moment in my career."

Their results "unambiguously showed us that the active site is built exclusively out of RNA," Ban says. This gave further support to the evolutionary RNA world hypothesis, which holds that the key molecules in primitive cells were not proteins but RNA. "This was in a way the moment where you could see back 4.5 billion years into ... evolution to the most primitive organisms and understand something about life on Earth," Ban says. Their results made the cover of Science in August 2000--with two back-to-back articles.

"Nenad's key qualities were his total commitment to the project, and his deep understanding of crystallography, without which we might not have prevailed," Moore writes.

Independence on the fast track

Ban was able to establish his research career thanks in part to some key fellowships, and his efforts have been further rewarded with some prestigious awards. When Ban first started at Yale, he obtained a fellowship from the Damon Runyon-Walter Winchell fellowship. Three years later, he had secured an assistant professorship at the Swiss Federal Institute of Technology, Zurich (ETH Zurich) in Switzerland.

But at that point, Ban wasn't quite ready to let go of his project at Yale. He decided to delay starting his own group for a year and a half, the time he estimated he needed to solve the structure of the ribosome. During that period, Ban was supported by a Burroughs Wellcome Fund Career Award, which allowed him to stay in Steitz's lab with a research scientist position and his own funding. Finally, in fall 2000, with his Science papers hot off the press, Ban set off for Switzerland with his wife, Eilika Weber-Ban. She had been doing a postdoc at Yale at the same time, in protein degradation, and subsequently started an independent scientific career at ETH Zurich.


(Photos courtesy, Nenad Ban)
Nenad Ban with some of his group members at ETH Zurich.

Today, Ban's group of 15 to 20 scientists still works on ribosomes, using a combination of crystallography, electron microscopy, and biochemical experiments to focus on what happens to newly synthesized proteins as they get folded and released by ribosomal complexes. Ban also turned his attention to fatty acids, and his group recently cracked the structure of the enzymes responsible for synthesizing fatty acids in yeast and then in mammals.

"They are solving interesting structures at an amazing rate," Moore writes. In 9 years, Ban's group has published 13 papers in Science and Nature. Ban won the Newcomb-Cleveland Prize from the American Association for the Advancement of Science (publisher of Science Careers) for his 2000 Science papers, the Friedrich-Miescher Prize of the Swiss Society for Biochemistry in 2004, and the Rössler Prize of ETH Zurich this year.

By providing the structures of basic cellular elements, Ban has injected new life into old biological problems. "It really opened up a whole new way of studying an old field," says Ban, who became a full professor, at the age of 41, in 2007. These structures have "enabled a lot of researchers in these fields to initiate structure-based functional studies." 

But Ban's greatest impact remains in the ribosome field. "All subsequent structures of the whole ribosome or other [large] subunits have depended on this structure" that Ban produced, "and it was a tour de force," writes Ramakrishnan, who has never collaborated with Ban. "As with some other ribosome groups, we have a friendly sense of rivalry. He is certainly someone I fear."

Elisabeth Pain is contributing editor for South Europe.

Elisabeth Pain is contributing editor for Europe.

10.1126/science.caredit.a0900089