A Quiet Scientist Returns to His Roots.

Tiago Fleming Outeiro

When he was in training to become a researcher, Tiago Fleming Outeiro took every opportunity he could find to expand his horizons. He left his home to earn a Ph.D. in the United Kingdom, followed by a postdoc in the United States. Interested in the fundamental biology of real-world problems, he accumulated a wide range of research skills to better investigate the molecular mechanisms at play in neurodegenerative diseases like Parkinson's and Alzheimer's. He also ventured away from fundamental science, participating in two start-up companies aimed at translating his discoveries (and the discoveries of others) into therapies.

Today, Outeiro says he is "still convinced that ... [he] made the right choice" in coming back to Portugal, and others seem to agree.

But when the time came to lead his own research group, he went back to his roots. Outeiro, 32, now largely takes a fundamental approach to neurodegenerative diseases, in keeping with, as he puts it, his "inner desire to learn and to understand biology at a deeper level." He set his sights on a faculty post in his home country--Portugal--which today offers good opportunities for early-career researchers. "I thought it was a step forward and not a step backwards or sideways, and that was important for me because I didn't want to compromise on the quality of the research that I was going to be doing," Outeiro says.

A quiet confidence

Outeiro "is highly self confident, perfectly aware of his quality, and ambitious," Maria de Sousa, a Portuguese group leader who returned home 25 years ago and has known Outeiro since his graduate days, writes in an e-mail to Science Careers. He has "a sort of quietness that comes with knowing."

Outeiro was drawn into the field of neurodegenerative diseases by the epidemic of mad cow disease Europe was grappling with at the time. The disease piqued his interest "because it was unconventional in the sense that it was not caused by either a virus or a bacteria or any of the conventional infectious agents," he says. In 1999, supported by a scholarship from the Portuguese Foundation for Science and Technology, he flew to the United States to begin work on a Ph.D. at the University of Chicago in Illinois with Susan Lindquist, whom he admired for her work in the field.

Protein misfolding and aggregation had been identified as a major factor in mad cow disease, and research using yeasts as model organisms played a large role in those findings. So Outeiro began using yeasts to investigate the role of protein misfolding in another neurodegenerative disorder: Parkinson's disease. He carried out genetic studies, looked at encoded proteins, and did high-throughput screens of small-molecule libraries seeking compounds with the potential to interfere with the disease. In addition to yeasts, he used the worm Caenorhabditis elegans as a model organism. Using such a broad range of approaches "enabled me to get a very good overview of different techniques and different organisms that can be used to study complex problems in biology," Outeiro says. His Ph.D. research led to six papers, including back-to-back publications in Science, and three patents.

By the time he finished his degree in 2004, the Lindquist lab had moved to the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. Lindquist was starting a biotech company called FoldRx Pharmaceuticals Inc., which partly relied on Outeiro's findings to develop novel therapies for protein-misfolding diseases. "So after I finished my Ph.D., I spent a few months working at the company to help [with] transferring the technology," Outeiro says.

"I had the opportunity to go and talk to venture capitalists, to talk to the CEOs of companies, to understand how the whole process of starting a company is done," Outeiro says. He values the experience but says, "I knew that what I wanted to do afterwards was to continue in science." He lined up a 3-year postdoc at Harvard Medical School's Massachusetts General Hospital and a Tosteson fellowship from the Massachusetts Biomedical Research Corp. "My goal was to go and learn other aspects, other techniques, other tools so I could get a broader view" of neurodegenerative disease research.

During his postdoc in Bradley Hyman's lab, Outeiro applied novel imaging techniques to understanding how conformation changes in proteins can cause neuronal dysfunction in Parkinson's and Alzheimer's diseases. "We found that, contrary to what people had thought until not too long ago, the big protein aggregates that are found in Parkinson's and in Alzheimer's might actually be protective," Outeiro says.

At about that time, Outeiro and several friends founded the BioEPI Clinical and Translational Research Center, a start-up company in the Lisbon area. "In Portugal, we don't have a lot of ... companies that do translational research, so the goal was really to apply our knowledge to the clinical field and to be able to establish a bridge," Outeiro says. He left the company after a year when it grew away from his interest in neurodegenerative diseases.

Back to roots

As his postdoc neared an end, Outeiro sought a way to come back to both fundamental research and Portugal. He declined an offer to stay longer at Harvard because if "I had stayed in the U.S. on a tenure-track position for another 5 or 6 years, then ... my whole life was going to be more stabilized and then it would be much more difficult to come back to Europe."

In recent decades, three new life-science institutes were created in Portugal at which "competition to get in is as tough as anywhere else in the world," says de Sousa, who 25 years ago left a principal investigator (PI) position at the Memorial Sloan-Kettering Cancer Center in New York City and today chairs the Human Genetics and Genetic Disorders department at one such Portuguese institute, the Institute for Molecular and Cell Biology in Porto. In 2007, Outeiro accepted a 5-year junior PI position in another of those new institutes, the Institute of Molecular Medicine (IMM) in Lisbon.

The offer was modest: lab space and enough money to pay one technician. In Portugal, job opportunities for scientists from abroad are much better than they used to be 25 years ago, but there still is "no decent seed money or a reentry funding policy, which is a great pity, because everything else makes us feel that we are becoming a 'normal' scientific country," de Sousa says. So Outeiro had to find money to establish his lab. By the time he joined IMM, he had secured research grants from the Calouste Gulbenkian and the Michael J. Fox foundations, two awards from the Portuguese government, and a Marie Curie International Reintegration Grant from the European Commission.

Today, five postdocs, four Ph.D. students, one master's degree student, and two technicians staff Outeiro's Cellular and Molecular Neuroscience lab. In addition to protein misfolding, the lab has research projects focused on the connection between aging and neurodegeneration and on the mechanisms by which toxic substances cause neuronal dysfunction and cell death.

Despite the fundamental focus of his work, Outeiro tries to "keep in mind that the problems we are trying to tackle in the lab are ... not just fundamental problems. ... These are problems that are actually affecting millions of people all over the world," he says. "Maybe one day we will actually be able to ... help develop novel treatments for the patients."

Today, he is "still convinced that I made the right choice" in coming back to Portugal, Outeiro says, and others seem to agree. Last year, he received a prize from the Portuguese Society for Neuroscience for the best scientific article in 2007, an Aging Research Prize from the Portuguese Society for Neuroscience and Pfizer, and an Installation Grant from the European Molecular Biology Organization.

Despite these successes, Outeiro seems determined to keep contentment at bay. Once you start to be satisfied with your accomplishments, "you're probably not going to be as productive or as intense in what you do as you should be," he says.

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