A man and a mouse

The cancer researcher who developed transgenic mice has won the Lautenberg Center's Shacknai Award.

cancer cell 88 (photo credit: )
cancer cell 88
(photo credit: )
His grandfather, father, sister and wife all received medical degrees, and so did Prof. Rudolph Jaenisch - but mankind is lucky that he was so bored by the University of Munich's medical school that he went into biological research after graduation. The German-born Jaenisch, one of the world's most prominent cancer researchers, is a pioneer in transgenic science and establishing mouse models of human diseases. Not only did he create the world's first transgenic animal model, but he also conducted the first experiment showing that therapeutic cloning can correct genetic defects. The 64-year-old founding member of the Whitehead Institute for Biomedical Research and professor of biology at MIT came to Jerusalem last month to receive the 2007 Rabbi Shai Shacknai Award of the Lautenberg Center for General and Tumor Immunology of The Hebrew University medical faculty's Institute of Medical Research. The prize was established three decades ago by New Jersey Senator Frank Lautenberg in memory of his Jerusalem-born Conservative rabbi, who died of cancer at the age of 38. Winners must deliver lectures on their research when they receive the award. "THERE WERE overcrowded lecture halls. I did dissections in preclinical studies, but I really lost interest. I didn't like the way medicine was taught, or the whole environment," he told The Jerusalem Post in an interview just before delivering his Shacknai Memorial lecture. In his last year of medical school in 1967, Jaenisch admitted, he found it so difficult to concentrate on lectures that he didn't even bother going to class, depending on textbooks and lab work. Even before earning his MD, Jaenisch went to the famed Max Planck Institute of Biochemistry to conduct research and do his thesis on bacteriophages - viruses discovered almost a century ago that infect bacteria, and that in the 1960s became major experimental tools for molecular biology. After earning his PhD there, he went to the US for his postdoctoral work, picking as his mentor Prof. Arnold Levine of Princeton University (who himself received the Lautenberg Center's Shacknai Award in 1999). The Princeton geneticist had worked on bacteriorphage genetics and was using animal tumor viruses to study cancer; he received the Shacknai Award for discovering the p53 protein - a molecule that inhibits tumor development and whose disruption is associated with more than half of human cancers. But a couple of months after becoming his first postdoctoral fellow, Jaenisch was asked by Levine to run his lab, as the latter was going on sabbatical in Europe. "He let me do whatever I wanted. He was very generous," Jaenisch recalls. Reading an article by Dr. Beatrice Mintz (a developmental geneticist at Fox Chase Center in Philadelphia) on creating chimeric mice, Jaenisch went to see her. "I was doing research involving the injection of adult mice with SV40 (Simian vacuolating) virus found in both monkeys and humans. The virus gave the mice sarcoma, a type of cancer that develops solely in bone, cartilage, muscles, fat and other supportive tissues but never in organs such as the liver. Why, I wondered, didn't the mice develop another form of cancer from this virus?" Jaenisch speculated that the simian virus either was unable to infect liver cells or these cells managed to neutralize viral DNA after infection. Injecting SV40 into an early embryo, he thought, could introduce the virus into all cells of the resulting mouse, showing definitively whether the virus can transform only multipotent stem cells that can differentiate into a variety of cell types. Mintz was "very friendly but somewhat skeptical" about the possibility that his proposed experiment, which would require a lot of time and equipment, would work. But Mintz invited him to do it in her well-equipped lab, as did Levine in his own when he returned from sabbatical. Jaenisch succeeded in isolating SV40 DNA at Princeton and then brought it to Mintz, who generously advised him on how to isolate and culture early mouse embryos. "Being introduced by her into mouse developmental genetics has been one of the most important experiences in my career," he says. Then he injected simian virus into embryos and implanted them into adult female mice who served as surrogate mothers, but the baby mice they delivered seemed completely normal. "I didn't know whether viral integration took place in the embryos," he remembers. A lab test called Southern blotting that could have shown genomic DNA had not yet been developed, so Jaenisch was unable to see if the SV40 genome had become part of the mouse genome. "I was very naive. I thought that if you just inserted genetic information into very early embryos, that could solve the problem." THEN HE accepted an offer from the Salk Institute in California to continue his work. Biochemist Tony Hunter and geneticist Paul Berg advised him to make DNA from a template and use radioactive DNA as a probe for SV40. A few months of work brought success: Jaenisch could see that the virus had indeed become part of the mouse genome, making the rodents in his lab the first retrovirus-mediated transgenic mice (even though the term "transgenic" had not been invented yet). "The DNA was really there, but it had been 'silenced' so the mice didn't get tumors from the virus, though they could transmit it to the next generation," he explains. The key technique he developed - known as epigenetics - became an important tool for developmental biology and cancer research, and aroused enormous interest among researchers and clinicians alike. Epigenetics is the study of epigenetic inheritance - a set of reversible heritable changes in gene function or other cell phenotype that occur without a change in DNA sequence (genotype). These changes may be induced spontaneously in response to environmental factors, or in response to the presence of a particular allele (any one of a number of viable DNA codings occupying a given position on a chromosome). "Epigenetics is very fashionable today, and is recognized as one of the major issues of developmental biology," says Jaenisch, who spends some of his free time trekking in the Himalayas or white water rafting. "It was esoteric, but now is very important. If you read text, for example, it is formatted with all the spaces and commas. But it you remove all these, the text becomes unreadable. Epigenetics makes the genome readable. Nuclear transfer and cloning are all epigenetics. The genes are there but not readable, so they have to be formatted or reprogrammed," Jaenisch continues. LIKE ALL researchers, he knows science involves adding another brick to the wall of understanding. "Science is such a cooperative enterprise. You have to use other people, because you can't do it all alone. Knowledge and data must be shared, and with the Internet, this exchange is much easier." Today, Jaenisch and colleagues use mice cloning frequently, and the technique has much influence in trying to answer the question of what part of a cancer cell phenotype can be reversed, stopping wild multiplication of the cells. Cancer usually begins with a mutation in an oncogene or tumor suppressor gene. Since it is believed that epigenetic factors - which are not genetic mutations - can decide parts of a cancer cell's phenotype, Jaenisch and his team thought they might be reversible. They inserted the nucleus from a mouse melanoma (skin cancer) cell into an egg whose nucleus had been sucked out, and then collected stem cells from the resulting embryo. They placed these stem cells into healthy mouse blastocysts, causing many to become healthy adult mice. This experiment demonstrated that the melanoma nucleus had been "reprogrammed" to promote the development of normal tissues. But when a melanoma cell is injected into an adult mouse, only skin cancer cells are created. This means that a cancer cell's phenotype is decided mostly by epigenetic changes, which are reversible. ENORMOUS PROGRESS in understanding cancer has been made in basic research, said Jaenisch. "But while we are still far from curing them all, there is a lot of progress in treatment, and this is very satisfying. My motive when I started was not to cure, but simple curiosity about how things work. As our cloning technology improves, we also will use mouse cloning to explore early stages in the development of cancer." Israeli research in molecular biology, he continues, "is of a high quality." I have had Israeli post-doctoral students in my lab, and I'm getting another one next month from Hadassah." As a leading researcher in therapeutic cloning - the transfer of genetic information from one cell to an unfertilized egg whose DNA has been removed - Jaenisch is totally opposed to reproductive cloning, which theoretically could make copies of humans. He appreciates the fact that human embryonic stem cell research aimed at therapeutic cloning - unlike in the US or Germany - is carried out in Israel with very few restrictions because it does not contravene Jewish law. "I live and work in America, but I feel more German than American, and Boston is a rather European-type city. In Germany, it is very hard to do human embryonic stem cell research today. And in the US, [President George] Bush [who has prohibited the use of federal funds for research on human embryonic stem cells outside existing cell lines] has had such a negative influence... not only in science." Jaenisch was "very pleased and honored" to win the Shacknai Award, which doesn't come with a large amount of money but is considered very prestigious. He will add it to his shelf, along with the first Peter Gruber prize in Genetics (2001), the Robert Koch Prize for Excellence in Scientific Achievement (2002), the Charles Rodolphe Bruphacher Foundation Cancer Award (2003) and numerous others. Four years ago, he was elected to the US National Academy of Sciences. Since five Shacknai Award recipients have gone on to receive the Nobel Prize (one received the Nobel and then the Shacknai) Jaenisch is in good company. At the Lautenberg Center, they know how to pick winners.