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Farmer's son cultivates a career in translational research

Robert Kralovics (CREDIT: CeMM)

In high school in Czechoslovakia in the late 1980s, Robert Kralovics raised fish for fun. The son of a farmer of Hungarian descent, he thought fish farming would make a sensible career. What really captivated him, however, was genetics: Scientist and genetics pioneer Gregor Mendel had been a local and was practically a "national hero," Kralovics says. Kralovics used his fish to win a national science competition, which landed him a coveted spot in the genetics program of one of the country's top universities.

With English as its working language, CeMM's strategy has been to recruit promising young scientists from around the world and give them the best infrastructure.

He would not become a fish farmer, but Kralovics, 40, still traces his character as a scientist to his origins as a farmer's boy during the Communist regime. Operating under communism made him resourceful, gutsy, and acutely aware of the privileges of working on the most pressing and competitive problems of the day. Farming made him pragmatic, ultimately attracting him to the real-world problems of translational medicine. Today, Kralovics leads his own lab at the Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences in Vienna, focusing on the genetics of a family of rare blood cancers known as myeloproliferative disorders.

Planting a seed

As an undergraduate at Comenius University in Bratislava (now in Slovakia), Kralovics believed his future as a scientist depended on the fall of the Communist regime. "It was clear to us that doing science during the regime was basically a dead-end career. I seriously considered illegally leaving the country if I had a chance," he says.

CREDIT: Robert Kralovics
Robert Kralovics and a big catch.

When the student protests started in 1989 -- Kralovics’s second year at Comenius -- he played a part. "I had a fantastic time organizing the student protests," Kralovics says. "It was about our future." Soon after the regime's fall, he got a fellowship to spend a semester in London, an opportunity he wouldn't have had under the regime.

When he finished his undergraduate studies, Kralovics and his girlfriend decided to marry and study in Brno -- she medicine and he genomics. Unfortunately, there was no program in human genomics at the Academy of Sciences of the Czech Republic in Brno, so Kralovics reluctantly switched to the biophysics program, where he could study plant genetics. "It was really a bit of a detour, seemingly, but I learned so much," he says. "At that time, plant genomics was a bit further ahead."

As Kralovics was finishing his Ph.D. in 1995, an unexpected chance arose to return to human genomics and escape the faltering Czech economy. Kralovics's undergraduate professor recommended him to Josef Prchal, a Czech-American hematologist working at the University of Alabama, Birmingham. Prchal invited Kralovics to work in his lab for a year. It meant putting his Ph.D. on hold, and his Ph.D. adviser was against it, but Kralovics said yes.

Fertilizing an idea

His partnership with Prchal was fruitful. Prchal's clinical knowledge allowed him to identify promising projects, which Kralovics tackled using his "unusual knowledge of laboratory techniques," Prchal, now at the University of Utah in Salt Lake City, writes in an e-mail.

One project in particular held a lot of potential. Myeloproliferative disorders, characterized by large quantities of abnormal blood cells in the body, were orphan diseases. Treatments were few, and the diseases were diagnosed by excluding all other options. Although not always deadly, these disorders could progress to acute leukemia and other serious conditions. Using PCR technology, Kralovics noticed an apparent link to genetic aberrations. Cloning a responsible gene could be a major advance.

At the end of the 1-year post, Kralovics returned to the Czech Republic to finish his Ph.D. But both Kralovics and Prchal were eager to keep looking for the genetic causes of the blood diseases, so in late 1996, after he tied up the loose ends of his degree, Kralovics went back to the United States. His wife abandoned her medical studies and joined him. After 2 years as Prchal's postdoc, Kralovics was hired as a non-tenure-track researcher at the university. In 2000, Prchal moved to Baylor College of Medicine (BCM) in Houston, Texas, and encouraged the department to hire Kralovics as a tenure-track professor, which it did. "I got my professorship pretty young," Kralovics says.

But even as Kralovics's career and research were advancing, he and his wife were growing unsatisfied. Kralovics was homesick for the rural landscape and pastimes of his youth. "In Birmingham, I was driving 5 hours to get to the first trout waters in Tennessee," he says. In Houston, whose climate he found stifling, even that wasn't available: "It was just a lot of muddy waters there."

Then in June 2001, Tropical Storm Allison caused hundreds of millions of dollars in flood damage at BCM, setting back many people's research, including his. Discouraged, Kralovics moved back to Europe, giving up his tenure-track position.

Transplanting his science

Immediately, hematologist Radek Skoda offered Kralovics a position at the Basel University Hospital in Switzerland. It was the equivalent of a senior postdoc position. His American colleagues treated setting up shop in Europe as "a major downgrade"; he watched his American network "cool off," he says. On the other hand, Europe's health system was more centralized, and through Skoda he almost immediately had access to 200 patients with myeloproliferative disorders, "almost five times what we had in Birmingham." Another 200 came when they partnered with Mario Cazzola of the University of Pavia in Italy. "In the U.S., you would have to go miles and miles and establish a big network to get the patient material for these genetic studies," he says.

With the extra patients, he soon made the breakthrough he had been seeking. Using microsatellite mapping and DNA sequencing, he found that an acquired mutation in a gene called Janus kinase 2 (JAK2), which helps produce blood cells, was central to the diseases. "It is a single mutation; that was the beauty of it," he says. "Everybody thought it would be easy to drug it, easy to make a small molecule and inhibit it, so you would immediately come up with a very rational cure for the disease." It also made diagnosis easier.

But there was a race to publish -- a race, he suspects, for which he himself fired the starter pistol when he presented preliminary mapping data in 2004 to a workshop full of "very intelligent" researchers with related data. Within 3 months in 2005, four articles came out in four different journals. His came out last, in The New England Journal of Medicine. Even though he had to share the credit, the high-profile discovery meant that he could again think about leading his own lab. Kralovics contacted Heinz Gisslinger, a hematologist at the Medical University of Vienna, only hours from his family in the Czech Republic. "I needed a partner that is very close to the clinic and has access to the patient material, because you can't really do genetics without the samples," Kralovics says.

This partnership established, he got a post as independent principal investigator at CeMM, a then-new initiative of the Austrian Academy of Sciences. With English as its working language, CeMM's strategy has been to recruit promising young scientists from around the world and give them the best infrastructure. He says his funding is "not terribly high by U.S. standards, but it's enough to sustain a small-sized lab. And I can really build on that."

Harvesting the fruits

Kralovics started at CeMM in 2006. By then, myeloproliferative disorders had become a hot research topic, so Kralovics had to figure out how his new lab could compete. Sharing an office, Gisslinger and Kralovics invested in creating a large bank of patient samples from which they could generate a diverse portfolio of projects. They hope to find several new drug targets; in particular, JAK2-like genes in the 35% of patients who don't have the JAK2 mutation and the genetic changes that cause some of the disorders to advance to leukemia. "We really managed to nail a lot of these leukemic drivers in our last paper," Kralovics says.

Finally, last year, Kralovics moved into his state-of-the-art lab, with panoramic views of the city, in the new CeMM building. He plans to grow to "at least a medium-sized lab" of about 10 people. He has won grants from the Austrian Science Fund and the MPN Research Foundation, which is funded largely by patients. "You feel an extra deal of responsibility [when] you're spending patient donations," he says. Last year, he won the Austrian Academy of Sciences's Ignaz L. Lieben Award, an achievement award reserved for researchers 40 and under in the former Austro-Hungarian Empire. "It was interesting to see that you can get some appreciation" for translational work, he says. "Usually, these awards go to real basic scientists."

Home for Kralovics and his wife is now a small wine-producing vineyard in the Czech Republic, not so far from where he grew up farming and fishing. "I used to say that science prevented me from becoming a farmer," he says. "Finally, at least this part of our life came back."

Chelsea Wald is a freelance writer in Vienna.

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