Pluri-Pioneer

Pluri–Pioneer With a simple insight and unselfish collaboration, Andras Nagy pushed stem cell research in directions it had never been before. © 2010 Icon Photography Inc./www.iconphotoinc.com Andras Nagy bent over his coffee-stained menu and began to scribble. Pentao Liu, a cancer geneticist from the Wellcome Trust Sanger Institute in the United Kingdom, watched from across the lunch table. It was January of 2008, and Liu had just given a talk at a conference near Munich, Germany about a DNA transposon system called piggyBac, a “jumping gene” first isolated from the cells of the cabbage looper moth. Now Nagy, a senior scientist at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto, had an idea. The piggyBac system is very efficient at inserting genes into cells and can be removed afterward, leaving no trace behind. Sitting in the café, Nagy quickly drew a series of crude circles, arrows, and triangles, a map of how the piggyBac system could be used to reprogram adult skin cells into induced pluripotent stem (iPS) cells. The first iPS cells were created using viral vectors to insert reprogramming genes, but viruses have the potential to mutate or alter the host genome, possibly causing cancer in iPS-derived tissues, so researchers have been eagerly searching for an alternative. Nagy believed he had one. “We were very excited about it,” he recalls. Fourteen months later, Nagy, Liu, and their international team were the first researchers to reprogram somatic cells without the use of viruses.1 Like other first-generation stemcell savants, Nagy did his training in an altogether different area. As an undergraduate in Budapest, he was a devoted mathematician. Until he met a girl. When a cute medical school student, who would later become his wife, invited Nagy to join her for a little experimental fun, he couldn’t resist. Together, they dissected a human brain. “It was a mixture of horror and excitement,” laughs Nagy. “It was a turning point in my life.” Nagy began to pack his schedule with biology and chemistry courses. In 1979, he completed his PhD in genetics at Lorand Eötvös University in Budapest, followed by a postdoc at the Center for Neurochemistry in New York. Nagy returned to his alma mater in 1982 and set up an experimental embryology lab, a first of its kind in Hungary. There, he made chimeras of embryos from fertilized and unfertilized egg cells to determine the roles of paternal and maternal factors in development. But within several years, Nagy wanted to do more. Because of his fascination with embryology, Nagy sent a letter to Janet Rossant, a renowned developmental biologist in Toronto. Rossant invited Nagy to join her lab as a visiting scientist at the Lunenfeld. “The original plan was to go for 2 years,” says Nagy. “In the fourth year, I bought a piano for my daughter.” He was staying. In 1994, Nagy accepted a position as senior scientist at the Lunenfeld, and a year later he was appointed a professor in molecular genetics at the University of Toronto. Thanks to Rossant, Nagy quickly became involved in embryonic stem cell (ESC) research and found his calling developing genetic tools to analyze ESCs. In early 2000, Nagy derived multiple new mouse ESC lines and created the first two Canadian human ESC lines, CA1 and CA2, still widely used in the country. “He’s a mouse genetics guru,” says Jim Woodgett, director of research at the Lunenfeld. “He’s got lots of incredibly complicated ways of knocking out genes or expressing them in different tissues.” At Lunenfeld, Nagy runs a transgenic facility to help researchers make new mouse models; he also maintains a freely available database of Cre transgenic mouse lines—knockouts made using an enzyme called Cre recombinase to splice DNA—on his Web site. “He’s got a tool kit which a lot of people make use of, including us,” says Woodgett. In addition to stem cell research, Nagy’s lab uses genetic approaches to study the role of vascular endothelial growth factor (VEGF) in blood vessel development, particularly during tumor formation. "He's a mouse genetics guru," says Jim Woodgett, director of research at the Lunenfield. "He's got lots of incredibly complicated ways of knocking out genes or expressing them in different tissues." But 2 years ago, Nagy made the switch from ESCs to iPSCs. After reading the landmark papers of Shinya Yamanaka of Kyoto University and James Thomson of the University of Wisconsin–Madison in 2007, Nagy decided to apply his ESC tool kit to iPS cells and quickly shifted 70 percent of his lab’s resources to the task. “My people reprogrammed rapidly,” laughs Nagy. Only a few months after Nagy’s serendipitous lunch meeting with Liu in 2008, he visited the University of Edinburgh to give a talk. There, Nagy met Keisuke Kaji, a young investigator at the university working on a new reprogramming vector system. Nagy asked Kaji about his work, but the young PI dodged the question. “I was very afraid, to be honest,” says Kaji. “He has twenty people and I have just two, and if he knew how the system worked, he could make it in 2 weeks.” To reassure him, Nagy told Kaji all about the piggyBac system, then said, “‘Now I told you everything, so you tell me yours,’” recalls Kaji. So he did, nervously. Kaji had recently designed a way to deliver Yamanaka’s four reprogramming factors to a cell using a single vector rather than four plasmids, as Yamanaka had. When Kaji finished speaking, it was clear to both men that each had half the puzzle: a single vector to deliver all four factors to the cell and a transposon system to remove them after reprogramming. Nagy returned to Ontario with Kaji’s plasmid in hand, and the senior scientist and rookie PI began speaking regularly, video conferencing and sharing data. “He was very generous and open,” says Kaji. When publication time rolled around, Nagy declined to be listed on Kaji’s paper, despite Kaji’s insistence that Nagy be last author. “He didn’t want to take any of the limelight away from his collaborator,” says Woodgett. “It was quite a selfless thing to do.” The collaborators published two papers, one from each lab, in an April 2009 issue of Nature and made headlines around the world.2 Last year, Nagy was the only Canadian to be named to Scientific American’s first annual Top Ten Honor Roll, sharing a page with US President Barack Obama. But despite his newfound fame, this scientist still makes the time to visit old colleagues and meet new ones. “I really consider visiting and talking to other scientists an essential part of my job,” says Nagy. “The best way to do science is when you’re excited about it and don’t care too much about who’s going to do it first.” References 1. K. Woltjen et al., “piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells,” Nature 458: 766–70, 2009. 2. K. Kaji et al., “Virus-free induction of pluripotency and subsequent excision of reprogramming factors,” Nature 458: 771–75, 2009.

Pluri-Pioneer

Pluri–Pioneer

With a simple insight and unselfish collaboration, Andras Nagy pushed stem cell research in directions it had never been before.

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Megan Scudellari

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December 2010

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