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Portrait of the Scientist Nadia Rosenthal’s science paints a promising picture By Steve Mirsky When Nadia Rosenthal donned the scientist’s white lab coat she became the black sheep of the family. Rosenthal’s father is an Emmy Award-winning composer who wrote the music for numerous films, including the classic The Miracle Worker. Her mother was a concert pianist. Her sister became a potter. Rosenthal herself is a serious painter. But while growing up in New York City, Rosenthal was inspired by a high school teacher to choose a life in science. “I didn’t realize how exciting science was until I was 15,” Rosenthal remembers. “I had an advanced-placement course with this incredible teacher who just launched right into metabolism and biochemistry and taught us as if we were able to understand it. And of course when you’re 15 you are able to understand it. You just have to be told that you’re able to understand it. So I became obsessed with the beauty and complexity of biochemistry. And I went home and told my parents that I was going to get a degree in science. I had spent quite a bit of time as a teenager learning how to paint, and they assumed I was going to go off and do that. They were stunned.” Rosenthal’s journey has taken her from one world capital, New York, to another, Rome, where she is a senior scientist at the European Molecular Biology Laboratory (EMBL). In that position, she is at the proverbial cutting edge of research. One area of study is stem cells, the pool of cells that have not yet been fated to exist as a particular cell type, such as liver or muscle. Rosenthal’s stem cell research provides insights into fundamental biological mechanisms and has potential value for the creation of treatments for injury and disease. Rome is not Rosenthal’s first European stop—she started college at the University of North Wales before returning to the United States to finish her degree at Harvard, where she also got her doctorate. While in England, she became fascinated with the questions of development and pattern formation. In the late 1960s and early 1970s, development was still thought of in what Rosenthal calls “fuzzy wuzzy” terms—models suggested that cells in one part of an organism emit biochemical compounds, and the relative concentrations of those compounds then influence other cells into choosing what kind of adult cell they would become. Rosenthal was looking for a more rigorous explanation of the relationship between an organism’s form and the forces that sculpt that form. Perhaps she never truly left art after all. At the time, all of biology was beginning to focus on genes—their DNA sequences, the proteins they code for, and the functions of both. Rosenthal recognized that to understand development, she was going to have to understand DNA. “Genetics was going to be the basis, the foundation, for the dissection of the more complex manifestations of cells. We had to know how genes worked. So I sacrificed myself on the altar of genetics and sequenced genes for five years.” Her work was part of the successful effort to sequence and clone the gene for insulin. Rosenthal’s half decade of doctoral work can now be accomplished in a single afternoon. “Yes, don’t remind me,” she says. “Without thinking twice, my students send out samples to be sequenced. And the sequences come back over their computers. They don’t even have to touch a tube. The question is, why do anything when in 10 or 20 years all the work that we’re doing now is going to be automated? And the answer is because there isn’t any other choice. We have to do the cutting-edge stuff so that we can eventually get to the point where it’s outdated.” During a postdoctoral fellowship at the National Institutes of Health, Rosenthal made a crucial discovery in genetics: she found the first human enhancer sequence—parts of DNA that regulate the turning on and off of actual genes. She went from there to Harvard to try once again to get a handle on issues in development, now with genetics as a guide. She decided to focus on muscle cells because they are easy to grow and study in a dish, where they progress through specific stages from undifferentiated precursor cells to fully mature muscle. Six years of running a lab at the Massachusetts General Hospital while a professor at Harvard led to new insights into development. “We were looking at which genes are getting turned on and off and which signals are turning which genes on and off—and how that changes over time during the development of an embryo. Because that’s what pattern is.” Scientists refer to the turning on and off of genes during development as orchestration. Perhaps she never truly left music after all. At Harvard, Rosenthal also revisited an old subject—insulin. She wondered if there was a way to make muscles less resistant to insulin, a common problem in adult-onset diabetes. A colleague advised her that it might be more fruitful to focus not on insulin but on another molecule, insulin-like growth factor 1, or IGF-1, which plays a vital role in governing growth. To see whether overexpression of IGF-1 might induce muscle to become more insulin sensitive, Rosenthal created a transgenic mouse that made an abundance of the compound. The animal was literally a Mighty Mouse. “It had enormous muscles,” she says. “And it stayed stronger longer, it was leaner and meaner, it withstood all sorts of muscle diseases. And over the years, we published a slew of papers looking at how the signals generated by this growth factor would have these marvelous effects without seeming to have any nasty side effects.” That research has continued across two continents—in 2001, Rosenthal and her English husband, Alan Sawyer, decided to go back to Europe, a decision helped by both being offered positions at EMBL in Rome. The investigations revealed that the beneficial effects resulted from the presence of stem cells—adult stem cells, not embryonic stem cells. Adult stem cells are pools of stem cells that, as their name implies, persist beyond embryonic development. Like their generally more potent cousins, the embryonic stem cells, they can produce a variety of cell types for growth, rejuvenation, and regeneration. Researchers are excited about adult stem cells in humans because they may provide a source of cells for research and therapy that are a perfect genetic match and do not require manipulating an embryo. “We looked at the way in which these muscles would regenerate when they were injured,” Rosenthal says. “And we saw that many more cells were being recruited into the injured muscle from the periphery.” The cells rushing in were bone marrow stem cells. “They’re probably doing something better, not different, from the normal regenerative process,” she explains. “By beefing up the whole system, we were able to generate mice that could essentially regenerate their muscles in disease and in injury. It was sort of miraculous. Then it fell to us to figure out what the mechanism is. Is it just an increase in what is going on in normal individuals, or are there qualitatively new things that are happening? And we’re still searching.” Rosenthal is now also looking at IGF-1 in heart tissue—the ability to regenerate heart muscle would open up new worlds of possibilities in the treatment of heart attack victims and other sufferers of cardiovascular disease. Much genetic research involves disrupting the function of a gene and observing the detrimental result to understand the normal function of the gene. “But I perturb the system to make it better,” Rosenthal says. “And it’s a completely different mind-set. It definitely resonates much more readily with the medical community than it does with the basic-science community. It’s an ‘oh wow’ thing for the basic scientist. Whereas the physician sees it as experimental therapy. And that’s what my lab does. Half of the lab is taking things apart to understand why they work. And the other half of the lab is trying to figure out ways in which we can harness that information to do some good.” More information 11/06
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