More to Come

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BY DEBORAH KOMLOS

The last decade or so has already seen a research-intensive Dr. Josef M. Penninger, to put it mildly. But the self-described “genetic engineer” is in the midst of another grand feat.

Earlier this year, Penninger left Canada with his wife and three young children to return to his homeland of Austria to head a new organization — the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (Vienna, Austria) — as its scientific and administrative director. Construction of the IMBA began in June with its opening scheduled for the summer of 2005.

Penninger’s prolific research record and landmark discoveries during his stay in Canada made him one of the country’s most lauded scientists. Among many other notable findings, his breakthroughs have included identifying a gene responsible for bone loss, and demonstrating the role of apoptosis-inducing factor in programmed cell death.

Deciding to leave Canada to pursue a new career direction was not easy, Penninger says, involving long and difficult negotiations and considerations, including many position offers. However, the allure of the IMBA post won him over.

“How often do you get the offer to build your own institution?” Penninger says. “The really interesting thing is, in many places where you go, you have to take over a team, take over people, and this is fresh. We start from the beginning. We can hire anybody. We can set our own structures.”

About 10 members of Penninger’s Canadian research team will be joining him in Vienna.

At the Top

Austria’s gain may be looked upon as Canada’s loss, but Penninger will maintain his links to Toronto through an adjunct professor role beginning in January in the departments of Immunology and Medical Biophysics at the University of Toronto (Toronto, ON), where he has been a professor since 1994. He will also continue research collaborations with the university.

Close to a year shy of turning 40, Penninger has a string of distinctions that in recent years has included receiving a Canadian Institute for Advanced Research (Toronto, ON) Young Explorers Prize in 2002, being named one of Canada’s Top 40 Under 40™ in 2000 and being listed among the world’s most cited scientific researchers by Science Watch in 2000 and 2001.

Though he is renowned for the science he has done, Penninger is also recognized for the breadth of his research, which has spanned several realms including osteoporosis, heart disease, cancer and understanding the mechanism of pain.

“The whole dream of our institute is we want to work with lower organisms, like a fly and maybe worm, with the idea that we have genetic models where we can do the whole genome screen,” Penninger says. Through this work, he says, all genes that control particular pathways can be identified, such as those involved in the development of obesity. The findings can then be applied to a mouse model.

Penninger plans to continue his current research streams in addition to targeting new areas. His group at the IMBA is addressing two main areas: immunology and heart diseases. The researchers are focusing on mouse genetics, dealing with gene manipulations to establish fundamental principles of development and basic mechanisms of disease pathogenesis.

The IMBA will house a central infrastructure, Penninger explains, where its researchers will have access to free equipment. Having this type of arrangement will greatly facilitate starting researchers, he says.

“After two years you touch your first pipette to do the first experiment,” Penninger says of these beginning scientists, who typically must struggle to find research funding. “Let them play and really give them jobs,” he says, “and not wait until they get their first grant and they hire their first students after a few years.”

In the quest to populate the IMBA with talented researchers, Penninger says it has already made a couple of hires, including filling the role of a junior scientist after receiving more than 100 applications.

“At the end of the day, it’s always two per cent of the people who do 98 per cent of really good work. So this is the two per cent we want, and then give them access to top-notch infrastructure,” Penninger says. But the IMBA will only give its researchers an eight-year contract. “This allows us to get permanently young blood, and because I think after eight years, you have made it anyway,” he says.

Penninger also plans to have a handful or so of graduate students at any given time. “The point is to educate good students,” he says, adding that he has already taken a few new students into his IMBA lab group.

What Penninger thinks distinguishes the IMBA is the scope of doing research on a large scale with an industrialized infrastructure, as well as its arrangement for permitting its researchers free use of the facilities. He feels these characteristics may set a precedent for the planning of similar institutes in Europe and even North America.

Taking Root

The IMBA will occupy the first five of seven storeys in a building that is costing approximately 45 million euros (approx. $70 million Cdn). Situated above the IMBA will be another Austrian Academy of Sciences institute now under construction, the Gregor Mendel Institute of Molecular Plant Biology. The entire building — about 20,000 square metres with approximately 9,000 square metres of net laboratory space — is being connected to the Research Institute of Molecular Pathology (IMP), which is financed by the drug company Boehringer Ingelheim GmbH (Ingelheim, Germany); together these form the IMP-IMBA Genome Research Center. While the IMBA is under construction, Penninger and his group have temporary offices at the IMP and temporary laboratories at the University of Vienna (Vienna, Austria), both of which are located in the city’s cluster of research enterprises called the Campus Vienna Biocenter.

The completed institute will have space for 150 to 180 people, Penninger says. It will also house a major mouse genetics facility, containing 20,000 cages, which will make the IMBA a “real global player in terms of facilities,” he says. The Austrian government is providing the IMBA with 7.25 million euros (approx. $11.25 million Cdn) as base funding per annum.

Penninger says it will be a rough two years. “It’s a little frustrating at the moment in terms of being bogged down by administration for something I’ve never been trained,” he says. “I mean, you’re not being trained as a scientist to deal with tax issues, how do you make the best structure that you get the most tax back, things like this. And this, of course, is essential for the institute.”

Nonetheless, Penninger is very enthusiastic about the planning, which has involved working with eminent architect Prof. Boris Podrecca.

Dealing with architectural details and deciding upon an institute’s internal organization may be novel tasks for Penninger, but one thing has remained steadfast — his passion for research, and in particular, the immune system. “When I was a student in Innsbruck, at the university, we had this really great teacher, and he was an immunologist, so everything else was rather boring. I kind of liked the idea of how do we interact with the environment and how the whole thing is set up,” Penninger recalls of his early days in immunology.

After writing his course exam, Penninger says he “kind of forgot about the guy” until one day he heard from a friend that that same professor — Dr. Georg Wick, chairman of the Institute of Pathophysiology at the University of Innsbruck Medical School (Innsbruck, Austria) — was looking for a graduate student.

Penninger approached Wick the next day and mentioned that he heard about the announcement. “He grabbed my arm and said this is the project, and you can start on Monday. And I started on Monday working on T-cells and I still work on T-cells 15 years later,” Penninger says.

Following his graduate thesis, which he began while completing medical school at the University of Innsbruck, Penninger moved to Canada. For four years starting in 1990 he did post-doctoral work at the Ontario Cancer Institute at Princess Margaret Hospital (Toronto, ON) and later became an associate scientist. He was also a principal investigator for eight years with the Amgen Institute — also at Princess Margaret Hospital — that used to be associated with Amgen Inc. (Thousand Oaks, CA) and is now called the Advanced Medical Discovery Institute.

Making it Worthwhile

Contemplating his achievements thus far, Penninger easily identifies those of which he is most proud.

“That there has never been anybody in my lab who went to work with me — student or post-doc — who has not done well, who didn’t get a good position . . . I hope it continues,” he says.

Penninger attributes this success to the teamwork. “We had a great team who could actually do it,” he says. “I always compare it to how everybody can think about making a house. But it takes people to actually build it, and that’s what I’m really proud of.

“In terms of science, I guess we did really neat things,” Penninger says. An accomplishment he highlights is the work on osteoprotegerin ligand (OPGL). In 1999, his lab, along with the Amgen Institute, identified OPGL, a gene that causes the body’s cells to deteriorate bone and in turn leads to severe osteoporosis. They also showed that OPGL regulates the formation of lymph nodes, which are the body’s source of T-cells that protect against infection, and that activated T-cells can induce bone loss.

What excites Penninger is the application of the findings, “that you can use this knowledge to help millions of people, that we figured out why arthritis leads to bone loss,” he says. “This started a whole new field of osteoimmunology.”

A product candidate using osteoprotegerin to block OPGL is in a Phase II clinical trial by Amgen Inc. for the treatment of osteoporosis, and Penninger says he is very optimistic about its success.

“What’s really satisfying is that most of the time there is this huge hiatus between what we’re doing and how things are being presented, what we can do now, what’s actually being done for humans. And in this case it’s really quite satisfying to see that your research is taken by a large biotech company to do some good. Hopefully there are no side-effects.

“So the question will be, how fast will this work for osteoporosis, because for osteoporosis you cannot really accept side-effects in healthy people, hoping to prevent something down the road,” Penninger says. “But there is so much bone loss in other diseases, rheumatoid arthritis — one in a hundred people get this . . . And cancer — there are a million people who have cancer that metastatizes into the bone.”

To give cancer patients dignity in life and to alleviate suffering is a strong motivator for his research, Penninger says. He witnessed the pain that his sister-in-law endured from breast cancer. The disease metastatized to her bones and recently took her life.

“You work on something, basic science, and most of the time it’s in newspapers, it’s all hyped — where do you go from there, where do you really go?” Penninger asks. “And then to see something, that maybe in 10 years somebody has breast cancer and they get up in the morning and they don’t scream because it hurts. And that’s what I find satisfying.”

The Road Ahead

More recent work about which Penninger is also very keen is on the DREAM (downstream regulatory element antagonistic modulator) gene. The results, published last year as a collaboration between his U of T group, The Hospital for Sick Children (Toronto, ON) and the Amgen Institute, involved genetically engineering mice to lack DREAM, which reduces production of dynorphin, a chemical made in response to pain or stress. As a consequence, the mice displayed a strong reduction in pain sensitivity.

“DREAM allows you to feel pain,” he says. “What we want to do now is make a DREAM blocker and then we can use it in humans . . . If it works, then it’s a home run, grand slam. The U.S. estimates a $100-billion loss a year because people cannot go to work because of chronic pain.”

Penninger points out, however, that sensation of pain is otherwise necessary. “It’s like seeing and tasting,” he says. “It’s essential because you need to know if something is hot or not . . . and that’s actually what DREAM does and allows you to do.”

Addressing the DREAM finding and others is the task of the first IMBA biotech spinoff, Vienna, Austria-based Apeiron Biologics Forschungs und Entwicklungsgesellschaft mbH, which has as its Canadian partner Borys Chabursky, president and founder of Strategic Health Innovations (Toronto, ON).

While much is on the go for Penninger in his new IMBA role, the move to Austria was not without some personal sacrifice. He says he misses the time he spent in Canada. Penninger and his wife had recently built their dream house in Toronto and were ready to stay for life. Their children, aged six, four and nearly two, were not taught German because he had not anticipated the move.

“But I don’t see myself coming back in the next five, 10 years,” Penninger says, “because if I start this, then put all my energy and sweat into building this institute, I really want it to get going.

“I like my work, I still have not given up. It defines us. I mean, how often do you get the chance in your life to actually do work you really like to do and if it pans out, it has some potential to help people,” he says. “That’s really the bottom line, I think, to do research where you can help people. And, actually, I always loved to work with the biotech industry . . . The next step must be biotech or pharma coming in, which makes the medication.”

Penninger pinpoints what is most important to him and what he hopes to still achieve.

“When I’m 60, I want to look back and say there’s no student who actually dislikes me and hates my guts,” he says with a chuckle. “This is the real accomplishment, that people stand up and say, it was a pleasure to work with the guy.”