Spotlight

Philipp Kaldis, Ph.D.
Head, Cell Cycle Section
Mouse Cancer Genetics Program

Spotlight Archive

Good science requires a life-long love of learning, a willingness to take risks, and lots of interaction with other scientists. These elements underlie the research advances made by Dr. Philipp Kaldis and his team (Cell Cycle Section, Mouse Cancer Genetics Program).

"I used to say that if I can get advice from anybody that helped me get a good result or have a successful experiment, I will be more than happy to take the advice," says Dr. Kaldis with a smile. "A lot of people think that once you have a Ph.D. you don't need to get advice from anybody because you have been educated and know a lot already. Yes, I do know a lot, but I still basically have to keep learning on a daily basis; I don't want to stop," he adds.

Early Mentors and Collaborators
Dr. Kaldis learned a lot from his father, a professor of physics at ETH (Swiss Federal Institute of Technology) in Zurich, Switzerland. "There were these huge machines [in his lab] and that impressed me as a kid," he recalls.

Although his fascination with his father's lab gave him an early interest in science, Dr. Kaldis focused on biology, thanks to his biology teacher, Dr. Brida Bütikofer. "She was a very funny, energetic woman and she made us feel at home," he says. In one class, Dr. Kaldis examined larval salivary gland DNA from flies, which can be seen through a microscope. "That was amazing and resulted in my first scientific picture/photo," he says.

Eventually, Dr. Kaldis studied biochemistry at ETH. His first two years at the Institute were challenging, studying mathematics, physics, and inorganic chemistry, before he could pursue the subjects that he really enjoyed: organic chemistry, botany, biology, and finally biochemistry. While he sometimes found the basic requirements frustrating, he believes that the core courses have served him well over the years.

At ETH, he also interned for two years in a lab as part of a 3-person student research team. The students gained valuable experience in working as a team on a long-term project, resolving conflicts, and interacting with different types of people. Dr. Kaldis believes this experience also contributed to his success as a scientist.

Continuing at ETH in pursuit of a Ph.D. in biochemistry, Dr. Kaldis worked in the Department of Cell Biology under Dr. Theo Wallimann, where he learned biochemistry and molecular biology, and characterized creatine kinase, an enzyme that catalyzes the conversion of creatine to phosphocreatine. Although the experiments were challenging, the dynamic interaction among the students and post-docs within the department resulted in a great working environment.

After completing his Ph.D., Dr. Kaldis became increasingly frustrated with his analytical studies of creatine kinase, mainly because it was difficult to discern a link between the biochemistry and what was actually happening in vivo. Accepting a post-doctoral fellowship with Dr. Mark Solomon (Yale University) enabled him to combine his expertise in biochemistry with in vivo analysis. Dr. Solomon's team was analyzing the yeast cell cycle and trying to purify a novel kinase from yeast. "That was just a wonderful project where everything came together," Dr. Kaldis remembers, smiling. He isolated this low-abundance protein, analyzed it in the yeast system, and then performed numerous genetic manipulations. Although Dr. Kaldis was finally able to purify the kinase, it turned out to be very different from the human homolog.

After this first venture into cell cycle regulation, Dr. Kaldis realized that he had a lot to learn about this field, so he focused on reading lots of papers and attending many meetings to get up to speed. Even today, he says, he still reads 1-3 papers per week, and believes this is essential to staying current in his field.

The Road Less Traveled
Soon after he arrived at NCI-Frederick in August 2000, Dr. Kaldis decided to start a project in another area of cell cycle regulation. "It was probably more risky than I actually realized at the time," he recalls. And, although it led him down another unfamiliar path, Dr. Kaldis has no regrets about his decision, because it resulted in new discoveries and collaborations. "Sometimes losing your way and taking a longer route is actually the only way to solve the problem," he says.

First, he mulled over several important, unresolved aspects of cell cycle regulation. For example, in yeast there is only one cyclin-dependent kinase (Cdk); however, in mammals there are many different Cdks. He wondered why the cell cycle is controlled by just one kinase in yeast, while in mammals, four or five are required for this same process.

Then, because the mouse system is much closer genetically to humans than is the yeast system, Dr. Kaldis decided to use a knockout (KO) mouse model to study Cdk2, a particularly important kinase. "This was really new territory for me," admits Dr. Kaldis, "but one of the things that is really wonderful about working here at NCI-Frederick is that a lot of investigators work on the mouse and were happy to give me advice." He discussed the project with NCI's mouse experts, Drs. Terry Yamaguchi and Mark Lewandoski (Cancer and Developmental Biology Laboratory), and Drs. Neal Copeland, Nancy Jenkins, Shyam Sharan, and Lino Tessarollo (Mouse Cancer Genetics Program). Using the new recombineering method developed by Drs. Copeland and Court and with the assistance of two post-doctoral fellows, Drs. Cyril Berthet and Eiman Aleem, Dr. Kaldis was able to develop a mouse KO model that shed new light on the role of Cdk2 in the cell cycle.

Previously, it had been thought that each Cdk regulated a different phase of the cell cycle (G1, S, G2, and M). Dr. Kaldis and his team showed that this was not true. "We learned that single knockouts of these genes are not lethal in the mouse," he explains. "This indicates that most of these genes (with the exception of Cdc2) are not essential, and that there is a lot of redundancy among these genes," adds Dr. Kaldis. In many cases, two different Cdks can perform similar functions: if one is knocked out, another compensates for the knocked-out gene. Although this redundancy is difficult to analyze because of the complexity involved, the lab has been able to identify which Cdk is compensating for the Cdk2 knockout. They have also shown that Cdc2 is important in the S phase. "For example, Cdc2 can take over from Cdk2 in S phase," says Dr. Kaldis. "But it doesn't work the other way around." What is so special about Cdc2 in mitosis? "That is our next question," says Dr. Kaldis. The team, which currently includes Cyril Berthet, Padamkumar VC, Weimin Li, Satya Ande, Shuhei Kotoshiba, Kristy McDowell, and Mary Beth Hilton, is now generating new KO models, but their focus remains on cell cycle analysis.

New Discoveries May Lead to New Therapies
The scientific advances made by Dr. Kaldis and his team and others may lead to new treatments for cancer patients. Until recently, the pharmaceutical industry invested a lot of effort into developing therapeutics based on inhibiting a specific kinase. "What became obvious from our work is that actually inhibiting just one of these kinases isn't good enough," says Dr. Kaldis. He thinks it may be more effective to combine two drugs that each inhibit more than one kinase; some companies are already moving in this direction.

Although a biochemist, Dr. Kaldis feels strongly that one of the best ways to go forward in science is to work with animal models. "We cannot understand how things are working if we can't study these processes in animals," says Dr. Kaldis. He also believes that collaborating with other scientists is essential. "Any effort to make collaboration easier should be done," he says. "I think especially because we are a little more isolated here at NCI, we have to step up our efforts to reach out to other researchers at other cancers centers nationally and around the world."

Dr. Kaldis, like many other scientists, is not in it for the money. "We are trying to generate data that will help us understand cancer and basically in the long run find a solution to cancer. There are so many people dying, I don't know a single person who doesn't know someone who has died of cancer," he says. "I come here every day because I believe that my work, together with other scientists, will contribute to the knowledge that we can use to cure cancer."

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