Swiss Structures

Justin Hession Photography /www.justinhession.ch

The snow had been falling steadily for hours by the time Kaspar Locher reached his lab at the Swiss Federal Institute of Technology (ETH), early on the morning of March 5, 2006. Looking out his fourth-floor window, he could see drifts accumulating around the hilltop campus on the outskirts of Zurich, and he knew he had to act fast.

For years, Locher and his team of structural biologists had been studying a family of molecules known as ATP-binding cassette (ABC) transporters - membrane proteins involved in shuttling a host of important substrates into and out of cells. ABC transporters are thought to contribute to drug resistance in cancer cells and antibiotic resistance in bacterial pathogens, making them potentially important clinical targets. The ETH group had already figured out how to express them in Escherichia coli, had purified the active protein in detergent solution, and had generated three-dimensional crystals suitable for X-ray diffraction analysis. The final step was to take the crystals to the synchrotron, normally an easy 45-minute drive northeast of Zurich, and try to produce some images of the transporters.

But Locher and his team weren't alone. "Several teams were working on figuring out how ABC transporters work," he says. "It was a race to get the first correct structure that would serve as a good model for eukaryotic ABC transporters involved in cancer drug resistance."

With the crystals ready to go and the thought of those other groups breathing down his neck, Locher wasn't going to let the snow get in his way. He grabbed his coat and a shovel, and began digging a car out of the tree-fringed lot.

Locher leads one of 10 research groups in the Institute of Molecular Biology and Biophysics at ETH Zurich (which locals pronounce "eh-teh-hah"). The 112 professors, postdocs, and students at the institute work in a modernist concrete building at the top of the Hönggerberg campus, about 15 minutes from the center of the city. In summer, the plate glass windows in many labs showcase panoramic slices of rolling countryside, with lakes and wooded hills receding behind the gnarled fir trees that dot the university grounds.

Justin Hession Photography / www.justinhession.ch

Dressed for the chill-room, Kaspar Locher looks for promising signs of crystal growth.

Through most of its 153-year history, the reputation of ETH has rested primarily on the work of its chemists, mathematicians, and physicists. Its list of 21 Nobel laureates, for example, is topped by names such as Wilhelm Roentgen, Albert Einstein, and Wolfgang Pauli. Of late, things have been going well for the university's molecular biologists, too. The most recent ETH Nobelist, for example, is Kurt Wüthrich, who earned the 2002 Nobel Prize in Chemistry for NMR methods he developed to determine protein structures in solution.

Normally, getting to the synchrotron is a much more straightforward affair for ETH researchers. One of the key perks of the institute is its easy access to the Swiss Light Source, built halfway between Basel and Zurich in the 1990s. Funding came from the Swiss government, the Paul Scherrer Institute where the synchrotron is based, and the ETH.

"It's a huge advantage," says Tim Richmond, a restrained, grey-haired American who currently holds the rotating post of head of the biology department at ETH. "It means good people come to us. We don't have to go finding them."

In the mid-1960s, the university created the Institute of Molecular Biology and Biophysics as a stand-alone entity. Since 1990, the Institute was folded into the Department of Biology, which also incorporates five other institutes and 12 independent chairs, in fields such as biochemistry, cell biology, microbiology, plant sciences, biomechanics, and sports physiology.

The structural reorganization was designed to create greater cohesion in the biological disciplines, and was generally a positive move, says Richmond. But it has created challenges. Until 2005, for example, the biology department did not have control over its own budget. And some of the more established researchers have found it hard to embrace the new structure, which reduced the independence of the long-established institutes. "At the level of the professors ... people feel the home base has been the institute," says Richmond.

But the recent shift has not dampened the university's reputation as one of the top places in the world for research in molecular biosciences. ETH "is a place that has managed to generate a superb scientific atmosphere," says Bernd Bukau, a professor of molecular biology from the University of Heidelberg in Germany, in an e-mail. "It is international with regard to students as well as professors, and great fun to visit." ETH "is an amazing place," concurs James Whisstock, a structural biologist from Monash University in Australia.

For Kaspar Locher and his team, the heavy snowfalls on that day in March 2006 meant the drive to the synchrotron was potentially treacherous. "There was a lot of anxiety," he remembers. "Later on they closed that part of the freeway."

But Locher's group managed to avoid mishap, arriving in time to take their allocated time slot at the synchrotron. Then, much to their surprise, the first crystal they tried returned exceptionally clear images. Within hours, they had enough data to show the structure of the multidrug ABC transporter at an unprecedented resolution of 3 Angstroms. "We were jumping up and down along the hallway of the synchrotron," Locher remembers.

Within weeks, they had submitted the results for publication, and when the finished paper appeared in Nature¹ in September 2006, it led to a complete rethinking of ABC transporter structure - and the retraction of five earlier papers on related structures.² (A software error had led Geoffrey Chang, the young US researcher who had published those earlier articles, to inadvertently mistake the handedness of the molecule.)

Locher, a steely character with short dark hair and rimless glasses, suggests that Chang's blunder might have been a result of rushing. Even if you are racing to the synchrotron, you must still adopt an almost obsessive caution, Locher says. "Perhaps you have to be a bit of a nerd," he laughs. "You have to be the kind of guy who would stand in front of a dart board and not leave until you throw a triple twenty."

In 2006 and 2007, Locher's publication was just one of nine that the institute's structural biologists landed in Science and Nature, in which they reported the structures of several important molecules, including fatty acid synthases from mammals and fungi. These papers were among the 300 refereed publications by the Department of Biology's employees in that period, according to ETH.

Several floors upstairs from Locher's office, Croatian researcher Nenad Ban agrees that diligence is key when tackling tricky projects. "I think it's very important not to succumb to the pressure to make decisions too quickly, or publish preliminary results," he says. "It is extremely important to have focused research that persists over many years."

Over cans of Coke Zero in an office filled with cactus-like succulents, Ban says the funding arrangements at ETH Zurich foster that kind of cautious deliberation. Tenured professors at ETH receive enough money directly from the university to pay their core research group, including salaries and consumables. Any grant money comes on top of that. The biology department's budget in 2006 was about 70 million CHF (~$64 million USD), of which roughly 20% was from third-party sources, university figures show. That internal dedication to funding has remained consistent: In 2003, the university budgeted 60 million CHF for the biology department, and roughly 55 million the year before.

The high level of internal funding allows ETH researchers to tackle risky, long-range projects that might otherwise be hard to fund, Ban says. He cites the work of Tim Richmond as a prime example. "He has been working for decades on some of the most difficult and important problems in structural biology, including the high-resolution structure of the nucleosome core particle,³ and his recent work on the chromatin fiber structure," he says.

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Tim Richmond, current head of ETH's department of biology.

Ban himself could also stand as an illustration of the benefits of this long-term approach. The bookshelves that line his office walls are scattered with candy-colored 3-D models of the molecules whose structures he and his team have painstakingly solved, including the large ribosomal subunit, whose structure he published at 2.4-Angstrom resolution in 2000,⁴ just before moving to ETH from Yale.

Across the hall from Ban's office, postdoc Simon Jenni, who came to ETH in 2001 after spending time at Imperial College London and working with Tom Rapoport at Harvard Medical School (and has since returned to HMS), leans his lanky frame against the stainless steel side of a fermenter and shakes his head contentedly. He's just been asked whether there are any pieces of equipment he wishes his laboratory had, and the answer is a simple "no." On a tour of the lab, he points out protein purification systems, ultracentrifuges, and cool rooms that are essential to the work of a structural biologist.

"In terms of equipment here for crystallography, it is absolutely superb," he says as we head into the chilly confines of a crystallization room, where students pipette drops of protein solution into wells in air temperature kept constant within half of a degree. "We can do everything on this floor."

Jenni, whose strong jawline is blurred with a deep 5 o'clock shadow, was an author on several papers in 2006 and 2007 that revealed the high-resolution structures of fungal and mammalian fatty acid synthases.^5-7 (See "An abattoir saves the day.")

Ban's arrival in Zurich marked another change for ETH. He was the first tenure-track assistant professor to be appointed at the university. "At the time I interviewed at ETH there was no tenure track program," Ban says. "Since I had tenure-track offers from top places in the US, the ETH president at that time, Professor Olaf Kuebler, decided to introduce a program."

That program, which later garnered funding from companies such as Hoffmann-La Roche, has provided startup funds for a number of assistant professors hired since then. "I felt it was done very professionally and was very much modeled on the successful assistant professor tenure-track schemes in the US," Ban says.

Roche's ongoing involvement included support for five positions for assistant professors from 2000 to 2005. The Roche Research Foundation also gives grants to various research groups within ETH, and the company supports dedicated instrumentation for structural biology at the synchrotron at the Paul-Scherrer Institute.

A spokesperson for the company says the grants come with no requirements, and ETH is free to choose the scientists it appoints to company-funded positions. "The overall reason for this support was the excellent scientific reputation of the ETH Zürich," she says.

Lunchtime at the Hönggerberg campus of ETH often involves a trip to the canteen ("mensa" in German). The mensa nearest the Institute of Molecular Biology and Biophysics is a large room lined with what looks like original 1960s wood paneling, and floor-to-ceiling windows.

On a sunny Friday afternoon in the summer, the terrace outside is bustling with students eating under big white umbrellas, surrounded by lavender and other flowering shrubs. Nearby a man-made lake, a few students take the opportunity to recline on angular orange pontoons that drift slowly by.

It's a congenial place to take time out during the day, but researchers at the university say that on weekends and after hours the campus becomes a ghost town. With no on-campus accommodation, and limited options for obtaining sustenance in the evenings, ETH scientists have little incentive to stay there. "By improving things like accommodation, shops, and convenience stores, we might be able to get people to work on weekends," says Locher. "There is not the same level of drive as in the US."

It's an issue the university has plans to rectify with an ambitious scheme it calls "Science City." The idea, if it comes to fruition, is to build accommodation on campus, better integrate public transport, and encourage the general public to visit. "Science City takes over the good ideas of an American campus and adapts these to a European context," according to the university's vision.

In the meantime, postdocs, students, and the occasional professor have taken the social calendar into their own hands with a regular Friday happy hour. Sharing pitchers of cold Swiss lager, half-a-dozen structural biologists partake of the ritual, bantering in Swiss German, French, Italian, and English.

As six o'clock comes and goes, most make moves to head home. But one diligent soul says he is going back to his desk: His 6-year PhD was finally nearing its end, and he is defending his thesis on Thursday. "Have another beer," the others say. "You need to relax." At first he shakes his head: "I can relax next week." Eventually the cajoling succeeds, and he stays. "But just for a small one."