Rudolf Jaenisch's pioneering work in the fields of epigenetics and stem cell biology, along with his early work developing transgenic mice, caught our attention. Curious to know more, BioTechniques contacted him to find out about the ambitions, character, and motivations that led to his success.Research Risks and Career Rewards
Was there a pivotal event that shaped your career?
When I was a postdoc at Princeton University in New Jersey, I worked on tumor viruses in the laboratory of Arnold Levine. When injected into a mouse, the viruses created sarcomas, but not tumors in any other organ, which puzzled me. There were two possible reasons for this: either the viruses couldn't infect cell types other than skin cells or fibroblasts, or they were not capable of transforming other cell types. I was trained as a simple molecular biologist and had no experience with mammalian developmental biology, until I read a captivating paper in 1967 from an eminent developmental biologist, Beatrice Mintz. I was naive then and thought that I might be able to answer my question if I put the SV40 tumor virus DNA into early embryos. Excited by the idea, I called Dr. Mintz, who was friendly and invited me to visit her lab in Philadelphia. But when I initially suggested my idea to her, she was skeptical since no one had done this type of experiment before. So I left Philadelphia disappointed.
A few days later, she called me after considering the idea further and said I could do the experiment in her lab. I also discussed the idea with Arnold Levine who thought that it was a crazy experiment. But he was very generous and said that I could use his lab to prepare the DNA for injection on my own.
I commuted to Philadelphia in the late afternoons and worked there at night. Dr. Mintz showed me how to isolate embryos, make pipets, and inject DNA. Once I injected embryos with the SV40 DNA and got the mice, the funny thing was that I had no idea what to do with them.
Then I moved to my first faculty position at the Salk Institute in La Jolla, California and learned the technique of nick translation, which is a procedure for making radioactive-labeled DNA probes in vitro that allowed me to make the probes necessary to verify that the mice had SV40 DNA in their livers and brains. This assay demonstrated that these were the first transgenic mice, a result we published in the journal Proceedings of the National Academy of Science. The crazy experiment worked and completely shaped my career by introducing many new puzzles.
Where did these early studies on transgenic mice lead you?
Although the mice had the SV40 DNA in their livers and brains, I was amazed that they never developed tumors. I tried to determine if they had germline transmission, but was not successful. Now I know that I hadn't done the correct experimental tests, but at the time, I believed that I failed. Hung Fan and Inder Verma, two postdocs from the Baltimore lab, joined the Salk faculty, and introduced me to the leukemia virus system, which I decided to use next. After about a year of injecting and implanting embryos, several mice were born. I looked for the virus in the blood of the second generation mice to check for possible germline transmission. I remember this very well. When I looked in the microscope at the first ten offspring, four had the virus; leukemia was transmitted to the next generation. However, most viruses were silenced when introduced into the embryo and didn't produce leukemia, prompting our studies on epigenetic gene silencing in early development.
Two decades later, Dolly was cloned and I thought it was just fantastic because a mammary cell has the epigenetic state for milk production, not embryo development. The genes for embryo development are all silenced. But if you put its nucleus into the egg, everything gets reprogrammed and those genes for mammary function get silenced, while the genes for development get activated. That is all epigenetics and that reversal in programming is the most unbiased way to study it. We immediately established nuclear transfer in our lab, which led to proof-of-concept experiments for therapeutic cloning, research on the potential of embryonic stem cells, and studying induced pluripotent stem cells.
Is there anything unusual in your approach to science?
I am not afraid of risk. To get a grant now, you have to be concrete. Study sections do not allow you to propose outrageous experiments with a low chance of success. When I wrote my first grant and proposed making transgenic mice with a leukemia virus, the name for transgenic mice didn't even exist and I had no evidence that this would succeed. It was really a risky proposal. I have done many high-risk projects through the years, but I believe that if you have an exciting idea, you must live with the chance of failure and pursue the experiment.