Zurich Pulls in Chemical Talent

According to conventional wisdom, migration to the U.S. is draining Europe of its brightest scientists. But Zurich, Switzerland's largest city, appears to be opposing the trend as far as chemical research is concerned. In the past few years, its major academic institutions for chemistry--the Swiss Federal Institute of Technology, Zurich (ETH), and the University of Zurich (UZ)--have been attracting chemists born or trained in the U.S. or both.

Generous research support and a superb infrastructure have been the major draws. Another asset is the abundance of opportunities for industrial collaboration. Still another is Zurich's long-standing chemical tradition, enriched by what used to be intense rivalry between UZ and ETH that now has turned into close cooperation.

Kim Baldridge, a computational chemist at the San Diego Supercomputer Center, in California, and her spouse, Jay S. Siegel, a chemistry professor at the University of California, San Diego, are Zurich's most recent recruits from the U.S. Last year, both accepted positions at UZ.

The U.S.-to-Zurich trend may have been started by Steven A. Benner, who was a professor of bioorganic chemistry at ETH from 1985 to 1996. He is now a chemistry professor at the University of Florida, Gainesville. He left Zurich in 1997, when his wife, a computer scientist, accepted a position at Florida. "I was a trailing spouse," he tells C&EN.

Benner was the lone American chemistry professor at ETH until 1992, when James E. Bailey, a pioneer of biochemical engineering, moved his lab from California Institute of Technology to ETH. Sadly, Bailey passed away in 2001. Bailey's Caltech colleague, chemical engineering professor Jeffrey A. Hubbell, headed for Zurich in 1997 to lead the Institute of Biomedical Engineering, a joint program of UZ and ETH.

Also in 1992, François N. Diederich left the University of California, Los Angeles, to join ETH. Over the years, he helped recruit chemists Erick M. Carreira from Caltech, Peter Chen from Harvard University, Donald Hilvert from Scripps Research Institute, and Peter H. Seeberger from Massachusetts Institute of Technology.

"I never intended to leave the U.S.," Diederich tells C&EN. He was, in fact, finalizing a move to a major East Coast university when he received an invitation from ETH to fill a position. "I am from Luxembourg, and I would have liked to study at ETH, but my parents couldn't afford it. Here was a chance to go there as a professor," he explains. Although his negotiations with the East Coast institution were almost complete, "I told my partners there that I had to probe this offer."

Diederich recalls how impressed he was with how swiftly ETH made him an offer that he could not refuse. The school is small enough that all negotiations are made directly with the president, he says. "When the president says yes, it's yes."

Chen recalls a similar experience when he visited ETH in 1994 to discuss an offer. At the time, he was an associate professor at Harvard, waiting for "the notoriously rare promotion to full professor." He says he presented the ETH president a list of what he needed to do the chemistry he wanted to do for the next 10 years. The president agreed to the entire package, clinching the deal.

ACADEMIC VENTURE CAPITAL. The wish list included money for equipment, a number of personnel lines, and the so-called ordinary credit. A personnel line is a fixed budget item--consisting of salaries and benefits--that can be used to employ a secretary, a technician, a senior coworker, one or two graduate students, or one postdoc. The ordinary credit is an annual cash allocation to cover consumables. Together, the personnel lines and ordinary credit could support seven to 10 people.

These institutionally provided resources do not require applications or reports. Chen calls them academic venture capital. Others refer to them as unrestricted or free money. Whatever they are called, they allow researchers enormous leeway in deciding which projects to pursue.

The ability to get resources without peer review is the major difference between the U.S. and Swiss--and, in general, European--science, and it has been immensely valuable, Benner says. It's the reason that in the 1990s, "practically every major advance in DNA chemistry came from Europe." For example, the progress in understanding the prebiotic origin of ribose in nucleic acids due to ETH's Albert Eschenmoser could not have happened in the U.S., he adds. "He would have been very hard-pressed to get funding for that work at the same scale in the U.S."

For another example, Chen had been using laser spectroscopy and other physical methods to study reactive intermediates with carbon centers, and he wanted to start exploring organometallic systems and catalysis. "If I had written a proposal to do catalysis work, reviewers would have said that I have no track record in this area, and I would have been turned down," he says. Instead, he used unrestricted money to get started. Now, 80% of his group is involved in catalysis and organometallic chemistry.

Seeberger is investing academic venture capital in two areas: the role of certain glycolipids in disease and the possibility of developing glycolipid-based vaccines against HIV and tuberculosis. These projects are risky and speculative and would not be funded in the U.S. without preliminary results, he says.

"There's a treasure trove out there, but to get preliminary data, one has to gamble," Seeberger says. "If you go to the National Institutes of Health without data, it's a problem. They don't fund bright ideas. I'm not complaining, because I was well funded in the U.S. But sometimes you need to gamble on crazy ideas, and here you can do that."

At UZ, institutional funds are allowing Heinz Berke, a professor of inorganic chemistry, to pursue what he calls chemical hobbies--problems that are "far away from my research themes" in organometallic chemistry. One hobby is the study of ancient man-made pigments, particularly blue pigments found in Chinese artifacts, including the life-size statues that make up China's spectacular Terracotta Army [Angew. Chem. Int. Ed., 41, 2483 (2002)]. From time to time, he also investigates the structures of samples in UZ's Werner collection of about 2,500 organometallic compounds prepared by the students of Alfred Werner, UZ's first Nobel Prize winner (chemistry, 1913). Each sample is labeled with a structural formula, in Werner's handwriting.

"We tested one compound that we doubted very much because of the structure Werner proposed: two cobalts bridged by amido, oxo, and hydroxy groups," Berke says. "How could Werner have thought of this construction? He had no X-ray. We doubted his intuition." However, structural studies in collaboration with MIT chemistry professor Stephen J. Lippard proved Werner right. When Berke, Lippard, and a colleague published the findings, Werner and a student, Marie Scanavy-Grigorieff, both deceased, were listed as coauthors [Inorg. Chem., 40, 1065 (2001)].

Siegel views the academic venture capital as an institutional commitment in the creativity of its faculty. "Even your crazy ideas get a chance," he says. "If you can make them work, then a whole program may develop. If not, you can test other ideas."

With institutional funds, researchers here spend much less time in writing grants than do their U.S.-based counterparts. Nevertheless, everyone C&EN talked to has been actively competing for--and winning--external funding based on peer review.

"Writing grants is an extremely valuable exercise because it sharpens your ideas," Hilvert says. "And projects supported by grants are generally more productive because they have been thought through very clearly. But here, you also have unrestricted money that allows you to go into new directions. It's valuable to have both."

The downside to getting funds without peer review is that it could become easy for a lab to lose its edge. Benner points out that when he joined ETH, the faculty had some people who had not published anything significant in 10 years but still continued to receive resources. Unless one is extremely well disciplined, the natural human tendency is to slack off, he says.

INFRASTRUCTURE. Another outstanding feature of chemistry in Zurich is the infrastructure. "It's awesome," Carreira says. All the facilities needed to carry out chemical research effectively at a high level--such as spectroscopy, analysis, and synthesis--are available and operational, he says. Not having to always figure out where to obtain, for example, X-ray crystal structures, is attractive, he adds.

Siegel's newly renovated lab at UZ's Irchel campus gives an idea of Zurich's academic infrastructure for chemistry. One integrated unit occupying 5,000 sq ft includes 27 fume hoods; six instrument rooms--including a weighing room, an analytical room equipped with gas and liquid chromatographs/mass spectrometers; a spectroscopy lab for time-resolved fluorescence, UV-visible, and circular dichroism spectroscopy; a room with glove boxes and specialty reactors for procedures not suited for normal hood work; and an area for materials characterization by differential scanning calorimetry, thermogravimetric analysis, and other techniques. All instruments are connected to a central computer and can be accessed from anywhere in the lab.

Also included are comfort features, such as a Garderobe, or changing room, and a meeting room connected to a wireless network and equipped with computer projectors and a kitchen. Siegel says every new Ph.D. student in his group will be provided with a personal laptop computer. Students can sit in this room with a cup of coffee and connect wirelessly to the Internet. "The whole lab has a greater infrastructure than the entire chemistry department of many U.S. universities," he says.

UZ also has three special infrastructure features for chemical research: a greenhouse, an autoclave room, and a U.S. Food & Drug Administration-certified kilo lab.

The greenhouse currently houses some rare orchids, whose fragrances are of interest to UZ researchers.

The autoclave room has eight steel bays for high-temperature, high-pressure reactors, with plumbing for a choice of gases, interchangeable reaction vessels, and computer-controlled running and monitoring of reactions. Such a facility is uncommon in research institutions, according to UZ organic chemistry professor Hans-Jürgen Hansen. He had been using it to run reactions at supercritical fluid conditions. A group at the University of Leipzig has used the facility to test whether a nonsoluble dye could be applied to a particular fabric under supercritical conditions, he says. The Swiss flavor and fragrance company Givaudan also is interested in using the autoclave facility, he adds.

The kilo lab, formally called the Laboratory for Process Research, has a history of commercial use. It was the starter facility for CarboGen, a Swiss provider of chemical and analytical services that is now part of the U.S.-based chemical company Solutia. After CarboGen moved out, Cilag--a Swiss manufacturer of active pharmaceutical ingredients (APIs) and finished dosage forms that is part of the pharmaceuticals group of Johnson & Johnson--formally established and fully equipped the lab as part of its operations. In addition, the UZ-Cilag agreement called for Cilag to use the facility for postdoctoral training.

According to Siegel, who is also the lab's director, when the agreement with Cilag expired, UZ committed to the future of the facility as a real-life training ground for industry-bound Ph.D. graduates in an academic setting. The real-life component will come from an industrial partner, which will bring in commercial chemical development projects. One of Siegel's first tasks at UZ was to finalize an agreement with the current industrial partner, Azad, a Swiss developer and supplier of APIs and advanced intermediates.

What the lab makes can go directly into clinical trials. Because the lab pays its cost from its revenues, it must bring in enough work to at least break even. The association with UZ gives Azad access to infrastructure that companies of comparable size do not usually maintain, says Sebastian Gaupp, the lab's director of operations. The access "makes us very fast and very competitive," he adds.

Chemists trained on problems with real commercial pressures will be better prepared for the industrial world than those who move directly from an academic research setting, Siegel says. His dream is to establish the lab's reputation so that "maybe 10 years from now, the credentials of process chemists might be judged by whether they had been trained here."

Back in Siegel's research lab, refurbishing was completed in January. Cost of renovation and new equipment is several million Swiss francs. (One million Swiss francs is about $800,000.) That's typical of UZ's package for its current recruitment efforts, Siegel says. For example, Baldridge also received substantial funds to purchase hardware for a 128-node, 256-processor computer cluster infrastructure.

Baldridge has built a career as a computational chemist at the San Diego Supercomputer Center and as an adjunct professor of chemistry at the University of California, San Diego. During the past 15 years, she has risen through the ranks of SDSC, culminating with her appointment as director of integrative computational sciences. In that capacity, she has been leading a program to develop and apply high-performance computational tools for complex computational problems.

Last summer, for example, she managed the distribution of a 15,000-calculation computational chemistry problem to unused computing capacity in individual PCs or computer clusters located in four countries. Through technology she has helped develop, the task was completed in a couple of days instead of a couple of years. This type of computing--called grid computing--is spreading like wildfire, finding applications from drug discovery to earthquake simulation. And Baldridge is deeply involved.

That expertise came to the attention of a dean at UZ when Siegel was negotiating his move to Zurich. Without much ado, UZ created a position and offered it to Baldridge. When late last year Baldridge joined UZ as director of computational capabilities and applications and professor of theoretical chemistry, she also became UZ's first female chemistry professor. One of her first infrastructure accomplishments is a computer cluster with a computing capacity of three-quarters of a teraflop.

Baldridge has garnered external support for her computational infrastructure in addition to UZ's. She will be working with Wanda Andreoni, at IBM's Zurich Research Laboratory, on specialized IBM-supported computational hardware, which also will be set up at UZ. "The students are excited because that's where the next jobs are--in interdisciplinary, cyberinfrastructure technology," she says.

At San Diego, another of Baldridge's passions has been the Maria Goeppert-Mayer Symposium, which she founded (C&EN, March 31, 2003, page 25). This annual one-day meeting on the first Saturday of March showcases women as mentors as well as superb and dynamic scientists. It has been a hit with men and women. After this year, she will turn the symposium over to a core group in San Diego. In Zurich, with support from UZ and IBM, Baldridge is creating a similar symposium. If she can pull it off, the new symposium will have its inaugural meeting in June. It will be named after "a famous woman in European science," she says.

The support that Baldridge and Siegel have received reflects a readiness to invest in people that is rare in the U.S., Siegel suggests. Because professors are expected not only to run a lab but also to create broad, institute-wide programs, infrastructure and equipment are put in place to maintain those programs and enhance the researchers' intellectual growth. Students also benefit because they are exposed to diverse problems, not just to a professor's specific interests.

INDUSTRIAL COLLABORATION. Zurich abounds in opportunities for industrial collaboration. The city itself is home to dozens of chemistry-related companies. Nearby Basel is home to Lonza, Novartis, Roche, and Syngenta. And elsewhere in the small country that is Switzerland are Azad, Bachem, Clariant, EMS-Chemie Givaudan, Firmenich, Fluka, Siegfried, Senn Chemicals, and numerous others.

Contacts with industry are easier than in the U.S., partly because the country is small and everybody knows everybody. Swiss chemical and pharmaceutical companies also have been traditionally supportive of chemistry in Zurich through collaborations and funding of programs and projects.

Support also comes in indirect ways. A notable example is the Albert Werner Foundation, a private foundation that has supported talented young Swiss chemists through grants since 1944. According to Chen, who is also the foundation's president, Novartis, Roche, Lonza, Firmenich, Cilag, and Fluka together contribute about 99% of the foundation's funding "in a tangible sign of industry's commitment to young scientists."

In the 1990s, the foundation awarded five grants per year to candidates of the post-Ph.D. degree called Habilitation, who are roughly the equivalent of untenured assistant professors in the U.S. With a more U.S.-style tenure-track assistant professor system replacing Habilitation in the German-speaking academic community, the foundation has initiated the Alfred Werner Assistant Professorship, Chen explains. The total award per person is about 1 million Swiss francs ($800,000), enough for six years of salary and benefits. Martin Albrecht, at the University of Fribourg, was the first recipient. A second competition has been launched this year.

Another way that industry supports academic chemistry is exemplified by Siegfried. According to Siegel, this Swiss manufacturer of APIs and finished drugs has committed to establishing in UZ a symposium and prize to highlight advances in process chemistry.

Collaborations are established not only with big pharmaceutical companies but also with small biotechnology firms. Examples are the collaborations of UZ organic chemistry professor John A. Robinson with Polyphor, a drug discovery company, and with Pevion Biotech, a vaccine development company.

One of Robinson's major areas of research is the design of small molecules that mimic the surfaces of proteins in protein-protein interactions. Such mimics could disrupt protein-protein interactions involved in disease or could stimulate the formation of antibodies against infectious agents. They have potential for therapeutic and vaccine applications. Robinson is working with Polyphor to develop methods of preparing such small-molecule protein-surface mimics. And he is collaborating with Pevion Biotech to develop a synthetic vaccine against malaria.

The vaccine will consist of small molecules designed to mimic certain proteins of the malaria parasite. It will be delivered through flu-virus-derived virosomes--that is, virus particles lacking nucleic acids. Pevion Biotech has the expertise to make such particles.

The flu virus is highly immunostimulatory, Robinson explains. One can remove the nucleic acids inside the virus and install on its surface small-molecule peptide mimics. When such a viral package enters the body, it stimulates a strong immune response and produces antibodies against the peptides mimicking the malaria parasite. Studies with mice show that the antibodies not only bind to the malaria parasite but also inhibit its growth, he says. The next step is to see if the vaccine works in humans.

While industry supports academic chemistry in Zurich, Zurich's academic institutions are increasingly involved in the development of new commercial ventures. UZ, for example, has had many successes in helping launch new businesses.

Among them is Molecular Machines & Industries (MMI), the brainchild of UZ physical chemistry professor Stefan Seeger. The company makes single-molecule detection systems developed from research in Seeger's group. Seeger founded the company in 1998, while he was still at the University of Heidelberg, in Germany. When he moved to Zurich, the company rented lab space at UZ to develop products. The company is profitable, with annual sales of about $5 million, he says.

Seeger says the experience in starting up MMI has convinced him of the need for a chemistry program combining chemistry and business. Young scientists straight out of the university have no idea how a company works. Especially with start-ups, the pressure to bring product to market and to ensure quality is extreme, he explains. "Quality assurance is a word you will never hear in an academic lab, but it is so important in industry. And chemists should learn how to manage projects and understand how money flows," he adds. Earlier this month, UZ approved the formation of a new major--chemistry and business studies--based on Seeger's proposal.

HISTORICAL TRADITION. ETH and UZ have been the academic homes of many of chemistry's giants, some of whose fierce rivalries were well-known in Zurich's chemistry circles. For example, the animosity between ETH's Leopold Ruika and UZ's Paul Karrer, both Nobel-Prize-winning natural products chemists, is a famous one.

According to a story told to M. Volkan Kisakürek, the editor of the Swiss chemical journal Helvetica Chimica Acta, the two so intensely disliked each other that they couldn't stand sharing the same dentist, even though they did so unknowingly for almost 20 years. One day, however, Karrer asked to change an appointment to one that coincidentally had already been taken by Ruika. Unaware of the enmity between the two men, the dentist's receptionist informed Karrer of the situation. Karrer's response was, the story goes, "What? Ruika? I will never let into my mouth a hand that has been in Ruika's mouth before."

Both Karrer and Ruika were authoritarians, according to Kisakürek. The high quality of their chemistry was due in part to their strong personalities, he notes. "And interestingly, both published almost all of their work in Helvetica Chimica Acta."

Based in Zurich, Helvetica Chimica Acta is part of the Swiss chemical tradition and enjoys the support of the Zurich chemical community. Kisakürek believes the journal continues to be competitive for several reasons: It does not have page restrictions, it publishes full experimental results, and it is meticulously edited by Kisakürek himself. It is perhaps the only journal that insists on systematic names of compounds and publishes them regardless of how much space a full name requires. Contributors appreciate the practice, he says.

Kisakürek believes the journal is also attractive to the new generation of chemists. "I'm not intending to make the journal more fashionable--whatever that means--for the younger generation," he tells C&EN. "Helvetica Chimica Acta is a solid, traditional journal, and I will keep it that way."

The nine winners of the Nobel Prize in Chemistry that ETH and UZ together have produced affirm the excellence of chemistry in Zurich:

• ◾ Werner, 1913, for the structure and coordination theory of transition-metal complexes.
• ◾ Richard Martin Willstätter, 1915, for investigations of plant pigments.
• ◾ Karrer, 1937, for pioneering studies in natural products chemistry.
• ◾ Richard Kuhn, 1938, for work on carotenoids and vitamins.
• ◾ Ruika, 1939, for work on macrocyclic compounds, higher terpenes, and steroids.
• ◾ Hermann Staudinger, 1953, for discoveries in macromolecular chemistry.
• ◾ Vladimir Prelog, 1975, for work on the stereochemistry of organic molecules and reactions.
• ◾ Richard R. Ernst, 1991, for developing high-resolution nuclear magnetic resonance spectroscopy.
• ◾ Kurt Wüthrich, 2002, for developing NMR techniques to determine the 3-D structure of proteins.

In addition, Tadeus Reichstein, who was an associate professor at ETH from 1930 to 1937, was among the winners of the Nobel Prize in Medicine in 1950 for discoveries related to the hormones of the adrenal cortex and their biological effects.

Furthermore, Zurich cultivated the chemical talents of several foreign associates of the U.S. National Academy of Sciences currently listed under the discipline of chemistry: Ernst, Duilio Arigoni (structure and biosynthesis of natural products; mechanism and stereochemistry of enzyme-catalyzed reactions), Jack D. Dunitz (crystal structure analysis as a tool for studying chemical problems), and Albert Eschenmoser (structural elucidation and total synthesis of complex natural products; chemical models of biogenesis).

Zurich also fostered the chemistries of Dieter Seebach and André S. Dreiding. Seebach is renowned for developing organic synthetic methods and for being one of the pioneers in the field of folding oligomers (C&EN, July 26, 1999, page 39). Dreiding is the inventor of the stainless steel, skeletal molecular models that were indispensable in understanding stereochemistry and conformational analysis before the advent of personal computers.

Dreiding also founded the Bürgenstock Conferences on Stereochemistry. This tradition, although conceived in Zurich, has attracted international participation from the start. The first conference, held on May 2–8, 1965, focused on fundamental stereochemistry concepts and definitions; discussants included Derek H. R. Barton and Kurt Mislow. Through the years, the conferences have become increasingly multidisciplinary, reflecting the growing intersection of chemistry with other fields.

Their rich history notwithstanding, both UZ and ETH have gone through academic depressions.

"We had a quality problem," Berke says. "The university recruited people who had started as students and then stayed on until they retired, as was common before. The practice no longer exists. And in the past 10 years, the chemistry faculty has become internationalized."

Meanwhile at ETH, by the early 1990s Arigoni, Dunitz, Prelog, and Eschenmoser had retired or were nearing retirement, and the organic chemistry faculty was "decimated," according to Diederich. No one was accepting ETH's offers, either because they were going to people who were already high up in their organizations or because the offers were too conservative, he believes.

Benner, who joined ETH much earlier than Diederich, offers another explanation: a tendency of chemists "to eat their young." That happens everywhere, he says, but it is easier to do so in the hierarchical organizations of the German-speaking academic system. The recent spate of recruitment from the U.S. reflects a failure to develop and retain internal talent, he suggests.

At present, cooperation characterizes the interaction of Zurich's two chemistry faculties. In fact, in some European circles, the two are often referred to simply as the Zurich chemistry community, Carreira says.

Cooperation is most evident at the level of interpersonal relations, Hilvert says. Zurich is a small city, and either campus is easily accessible from the other. People often meet in seminars and public lectures. On a more formal level, the two institutions consult each other regarding recruitments. Representatives from one institution sit on the other's search committees, for example.

Recently, the two institutions agreed to recognize each other's chemistry courses and degrees as equivalent. Students can take upper-level chemistry courses offered by either department. B.S. graduates of one can enter the master's program in the other with no additional requirements. Diederich says these measures have been useful for ETH. Through UZ's strength in biology, ETH now offers electives in, for example, crystallography. Also through UZ's faculty of medicine and hospital, ETH's pharmaceutical science program, which is part of the department of chemistry and applied biosciences, has access to clinics.

In early February, excitement was in the air as the UZ science faculty selected a successor for Hansen, who will retire on Feb. 29. Soon, another U.S.-trained chemist will be joining the Zurich chemistry community. UZ will announce the appointment next month.

The U.S. system does a good job of developing talent, Benner observes. And there's no question that the current crop of U.S.-to-Zurich movers will not lose their edge and will continue to do excellent science, he says. "The question is whether they will train their successors. That's the test of all academic faculty."