A Young Scientist at the Forefront of Cell Reprogramming

Konrad Hochedlinger has yearned to understand how genes determine the development of organisms since high school, when he first learned about DNA. The direction of his career was further influenced by the cloning of Dolly the sheep, which was announced when he was an undergraduate. “I was very fascinated by the possibility to take an adult cell and recreate an entire animal,” he says. “I started … my Ph.D. because I wanted to understand how cloning works. … Back then, this was a very exciting question.”

Since then, stem cell research has advanced in a steady stream of important developments, leading to Science’s Breakthrough of the Year for 2008: the reprogramming of differentiated cells into stem cells or new kinds of mature cells. “There’s so much unknown about [stem cells], you permanently change the boundaries of biology by working in such a field,” Hochedlinger says. “Almost every new discovery you make is an interesting discovery.” Hochedlinger, who, at 33, is an assistant professor in the Department of Stem Cell and Regenerative Biology at Harvard University and the Massachusetts General Hospital in Boston, has been an important player in the field since his Ph.D. days.

An early fascination

Hochedlinger showed early promise. While earning a master’s degree in biology at the University of Vienna in his native Austria, he spent more than a year researching the function of genes in bone development and cancer in Erwin Wagner’s lab, which was located at the Research Institute of Molecular Pathology (IMP) in Vienna. “I was impressed by his personality,” Wagner writes in an e-mail to Science Careers. “He was always very industrious and organized.”

Hochedlinger met his Ph.D. supervisor during his year at IMP. After Rudolf Jaenisch gave a talk in Vienna on the cloning of mammals, Hochedlinger approached Jaenisch and asked about doing a Ph.D. in his lab. After a visit to Jaenisch’s lab at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, Jaenisch said ”Yes.”

In the spring of 2000, Hochedlinger started trying to make a mouse out of a fully differentiated cell in Jaenisch’s lab. Back then, it wasn’t clear whether the nuclear cloning that gave birth to Dolly was successful because it used rare adult stem cells present in adult tissues or because it used already specialized cells, as the cloners claimed. It was a risky project.

After a year and a half of experiments, no mice had been cloned, and success was not in sight. Jaenisch began to accept the failure of Hochedlinger’s experiments as a biological fact, and Hochedlinger started a backup project. Still, he didn’t give up on making a new mouse from an old one. “I really wanted to get it to work, so to overcome the frustration, I just read more, I talked to people, I tried to find alternative ways to do it,” he says.

He succeeded, cloning mice from fully differentiated cells. The work was published in Nature in 2002. It was conclusive evidence of the cloning of a mammal from fully differentiated adult cells. “It was a transforming event for me in that it got me more and more motivated and excited to stay in science” so that he could tackle the next big question, Hochedlinger says.

Hochedlinger’s backup project was also ambitious, and it too was successful. “We corrected an immune deficiency in mice by treating sick animals with custom-tailored embryonic stem cells that had been cloned from their own skin cells. This was a proof-of-principle experiment for so-called therapeutic cloning, the therapeutic use of nuclear-transfer technology,” Hochedlinger says.

Hochedlinger is quick to share credit for his accomplishments, especially with his mentor. Jaenisch “gave his students and postdocs a lot of freedom … [in] how to approach a problem and how to implement it as an experiment.” Along with his mentor’s encouragement, Hochedlinger says that this freedom was a major factor in the projects’ success.

After he got his doctorate in 2003, Hochedlinger decided to stay in Jaenisch’s lab because he felt it was the best place to “really learn the most about reprogramming and nuclear cloning,” he says. During his Ph.D., Hochedlinger applied nuclear cloning as a tool. As a postdoc, he worked to decipher the mechanisms at play. He investigated whether turning on Oct4, a gene suspected of being involved in cellular reprogramming, could reprogram adult cells back into their embryonic state. It didn’t happen, but the result was interesting: Oct4 activation in mice made adult stem cells multiply abnormally and become cancerous.

Programming an independent career

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Hochedlinger started applying for faculty positions in 2006 and soon had two offers: one from the Sloan-Kettering Institute in New York City and one from Harvard University. He settled on Harvard partly for the collaboration prospects the position offered him. Harvard “has such a rich stem cell group of people, and many of them work on complementary aspects of stem cell research, so you can easily engage in collaborations and learn more about your own field and somebody else’s field,” Hochedlinger says.¬†

Getting started as a principal investigator¬† was difficult, says Hochedlinger. He had to transfer many technologies from his previous lab, and in the stem cell field these are often delicate to set up. Becoming a manager was also a challenge. “Coming from your postdoc, you’re not really prepared to run your own lab.”

Still, it took him just 6 months to get the lab up and running. Today, the lab is productive, with four postdocs, two Ph.D. students, and a technician. “I was very fortunate to have colleagues who started their labs shortly before me, and they helped me a lot,” Hochedlinger says. His model, at least as far as the lab’s dynamic goes, is Jaenisch’s lab at the Whitehead Institute.

Since Hochedlinger started his faculty position 2 years ago, stem cell research has made still more breakthroughs. Researchers have been able to use a cocktail of four genes to directly reprogram differentiated cells into cells closely resembling embryonic stem cells–so-called induced pluripotent stem (iPS) cells–without using nuclear transfer or egg cells at all. Among those four genes was Oct4.

Recently, Hochedlinger has been using iPS cells as a tool for understanding how nuclear reprogramming works. The possibilities of the technology are extraordinary. In addition to helping understand disease by providing more powerful study models, “what this technology would allow you to do is reprogram a skin cell, for example, from a Parkinson’s patient … into a pluripotent cell and then in a petri dish redirect that cell into … a neuron” to treat that patient. An exciting moment for Hochedlinger came when Ph.D. student Nimet Maherali generated mouse and human iPS cells in the lab for the first time. Watching her produce this result, and get as excited as he was during his own big Ph.D. moment, was especially rewarding, Hochedlinger says. Later, Hochedlinger and his team generated iPS cells with a technique that doesn’t require viruses to introduce the four required genes. That’s a step toward therapy, Hochedlinger says, because the use of viruses disrupts the hosts’ genes and may cause cancer.

Hochedlinger, who in 2007 received the NIH Director’s New Innovator Award and this year was recognized as a Young Innovator Under 35 by the MIT Technology Review for his scientific achievements, sees many more big moments to come for the field. “It’s these unexpected [results] and these open questions in biology … that keeps me excited and I think will keep many of us excited in the years to come.”

Photo: B. D. Colen

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