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Renaissance Woman

Geneticist, artist, and bon vivant Nadia Rosenthal moved to Italy to make a go of the European Molecular Biology Laboratory's mouse biology program.

In 2001, Nadia Rosenthal (pictured left), a leading researcher in muscle gene regulation, left the ivory tower of Harvard Medical School in Boston to head a fledgling branch of the European Molecular Biology Laboratory in Italy. Her charge: to build up EMBL's mouse research center in Monterotondo, near Rome. The research campus is focusing on the rodent in order to understand human diseases and to uncover, among other things, potential strategies for regenerative medicine. Colleagues widely viewed the move as career suicide, Rosenthal says.

"Most people thought I had just lost it, gone off the deep end," she recalls. American scientists who "had only been to Italy for holidays and had seen a lot of inefficiency and crazy driving" doubted that it was possible to do serious science there, she says. Rosenthal, 50, is a petite, stylish woman with long brown hair and a fondness for big hats. Also an artist and athlete--she's an expert skier who hurtles down black diamond trails with ease--she sports an adventurous streak. She likes to quote a line from E. M. Forster's novel, Where Angels Fear to Tread: " 'Let her go to Italy!' he cried. 'Let her meddle with what she doesn't understand.' " "I have it on a slide, and when I go to the U.S., I always start my seminars with that," Rosenthal says.

A year and a half of meddling later, the EMBL mouse program is moving onto increasingly solid footing. By the end of the summer, Rosenthal will have expanded its faculty members from three to six, constructed a 900-square-meter mouse house for 35,000 rodents, set up most of the center's heavy scientific equipment, and established an administrative structure--and boosted the program's profile across Europe and in the U.S. "Monterotondo is now a substantial landmark in the mouse community, and not the least because she's there," says developmental geneticist Peter Gruss, president of the Max Planck Society, a nonprofit research organization based in Munich, Germany. With Rosenthal's tremendous energy and leadership, and her recruitment of additional top-notch investigators, the research campus is "a place to reckon with in science," he says.

Before Rosenthal arrived, few scientists had heard of the mouse center, says former Rosenthal postdoc Antonio Musarò, a molecular biologist at the University of Rome "La Sapienza." "But Nadia really has done a good job, because now, around the world if you talk about EMBL in Monterotondo, probably everybody knows about this institution."

Molecular biologist Eric Olson of the University of Texas Southwestern Medical Center in Dallas says Rosenthal is blossoming. "Boy, all the possibilities for disaster were there, but I think she's just done an amazing job," says Olson, who visited Monterotondo in May. "She has risen up in the scientific world, and I think she's going to become one of the most influential female scientists in Europe. She's already involved in all sorts of policy issues around Europe, and she's bringing a unique perspective because of her experience in the American system." Rosenthal, the only woman on a panel of a dozen scientists reviewing life-sciences grants for the European Union, has been weighing in on its current scientific agenda. And she is a key player in a transnational consortium of research groups that are working to characterize mutant mouse strains, a European Union initiative called EUMORPHIA.

At the same time, Rosenthal is continuing her research, which has focused largely on the genetics of skeletal muscle and heart development. More recently, she has also been investigating the loss of muscle mass that is seen in aging and in certain diseases--and the ability of a protein called insulin-like growth factor-1 (IGF-1) to reverse that degeneration.

Rosenthal's interest in science sprung, unexpectedly, out of an early passion for art. She grew up in New York City, a daughter of two classically trained pianists; her father, Laurence Rosenthal, is also a well-known Hollywood film composer. As a child, Rosenthal studied piano, classical guitar, and ballet. She began sketching as soon as she could hold a pencil. On family getaways to the coast of Maine, she captured shells, plants, and animals on paper. "I'd draw anything I could. I wanted to see if I could get it just right." Her parents even bought her a microscope so that she could get a closer look at her subjects. By age 12, she was studying Renaissance art. A few years later, she was taking lessons from a painter who worked in hyper-realism, the contemporary style of creating pictures that look as real as photographs.

Heart of an artist. Rosenthal drew this "Heart Carpet" to illustrate the cover of Heart Development, a book that she co-edited. Her design was inspired by 19th century Persian rugs woven by the Ashfar, a nomadic people of Turkish descent. Fields of cardiac tissue are represented in red. Progressively later stages of heart development are depicted running down the diagonals of the carpet, in two different colorways. [Credit: Adapted from Heart Development, Richard Harvey and Nadia Rosenthal, Eds., copyright 1998, with permission from Elsevier]

Then, when she was 15, Rosenthal took an advanced biology course in high school. "It wasn't the first advanced course I had taken, but this one just got in there, and it sunk in, and it never got out again," she says. Her science teacher, Mrs. Grimm, a former chemist, taught everything from phylogeny and evolutionary biology to the biochemical pathways of metabolism. Rosenthal was particularly intrigued by the recurring themes in nature that she had been drawing. What gave rise to the spiral designs in seashells, fiddlehead ferns, and sunflower heads? Why do some creatures, such as the sea urchin and starfish, show a radial symmetry, whereas others don't? "Those sorts of questions about general form, and the forces that shape them, were really something that just caught my fancy," she says. One day at a school, she had an epiphany: She would study the biology of pattern formation.

"I proceeded to march home and tell my parents that I was going to be a scientist, which really shocked them," she recalls. Her mother and father had arranged for her to interview at Sarah Lawrence College in Bronxville, New York, and Bennington College in Vermont, which at that time offered strong arts programs but no science. Rosenthal, by then obsessed with biology, was unsatisfied. A friend who was a Rhodes scholar suggested that she apply to schools in the U.K., where students could focus on one subject. Rosenthal took the advice and, in 1971, began studying biology at the University of North Wales (now the University of Wales) in Bangor. One rainy day, Rosenthal recalls, she was reading in the library and came across a popular science magazine. A picture of a child's hand, outstretched, was on the cover. "The title was 'How Does a Hand Know to Become a Hand?' [and] I said, 'Ohhh--that's it, that's it. That's the sort of thing I want to study.' " The article reviewed what scientists knew about the molecular underpinnings of pattern formation, including research on regeneration in the hydra. Rosenthal showed the magazine to her zoology teacher, who told her that the college wouldn't be able to teach her about this frontier of developmental biology because it was so new.

Trial by Fire

So in 1973, Rosenthal transferred to Harvard University in Cambridge, Massachusetts, lured by its large biology program. She did undergraduate research with developmental biologist Fotis Kafatos, who was studying the formation of eggshells by silk moths. Kafatos, who is now the director-general of EMBL, emphasized how important the emerging tools of molecular biology would be for unraveling the mechanisms that control development from a fertilized egg to a whole organism. Swayed by his logic, Rosenthal decided to pursue Ph.D. work in molecular biology after she graduated in 1975, also at Harvard.

She joined the lab of biochemist Argiris Efstratiadis, who was collaborating with molecular biology pioneers Tom Maniatis and Walter "Wally" Gilbert in elucidating the basic structure and evolution of genes. "It was very exciting," says Rosenthal. "One form of sequencing of DNA was invented in Wally's lab, and I was one of the people involved in testing it out and optimizing it. So I learned all of the ins and outs of molecular biology by being there when things were getting started." She was on the team that sequenced the first mammalian genes--those encoding insulin and globin.

As enthralling as the science was, however, the environment at the time was "cutthroat," Rosenthal says, because the Harvard researchers were in fierce competition with other world-class labs. "It was very, very pressurized. ... Graduate students were sort of cannon fodder. You got stuck in the lab, and you worked until you dropped, or until you revolted, or until you got out," she says.

The atmosphere was even more unfriendly for women. Ten students started in her graduate biochemistry class; five were women, and Rosenthal was the only one of them to finish. "Everyone else had dropped out. It was just too tough, too sexist, too competitive." After 5 years of intense pressure and a constant sense of underachievement--"because I never was good enough for the boys," Rosenthal says--she recalls being "pretty demoralized." After she completed her Ph.D. in 1981, she told herself she would try science for only a little longer. "If I didn't feel differently after two more years, I was going to get out."

Rosenthal took a postdoc position with molecular virologist George Khoury at the National Cancer Institute in Bethesda, Maryland. His group had just discovered the first enhancer, a stretch of DNA that controls gene activity, in the monkey virus SV40. The lab was racing against rivals to elucidate the nature of enhancers. But unlike her time at Harvard, Rosenthal says, "the next 3 years were just magic." She proposed hunting within the human genome for a different enhancer that had been already identified in a little-studied human virus called BK, which was similar to SV40. Khoury thought the idea was a wild goose chase, she says, but let her pursue it. After struggling with the project for a year, Rosenthal hit pay dirt: She found the first human enhancer. "The sense of individual discovery was so wonderful that it overrode my concerns of a year and a half before. And I was off to the races."

Tracking Patterns Into Aging

Rosenthal wanted to get back to developmental biology--to those patterns that had fascinated her as a child--and apply the genetic research tools she had learned. She decided to study gene regulation in the highly patterned tissue of skeletal muscle, which scientists had just begun dissecting at the molecular level. Returning to Boston in 1984, she worked first as a research associate and instructor in the cardiology department at Children's Hospital and then, starting in 1988, as an assistant professor at Boston University. In 1993, Rosenthal went back to Harvard, taking an associate professorship at the Cardiovascular Research Center at Massachusetts General Hospital East, in Charlestown.

Early on, when she was at Children's, one of Rosenthal's major sources of funding was the National Institute of Child Health and Human Development. But in the late '80s, low on money, the institute told her that it couldn't back her latest proposal, despite the high score it had won from the grant review panel. Rosenthal was in a panic. But she learned from a colleague that the National Institute on Aging was sponsoring research on muscle biology, because muscle loss is one consequence of growing old.

"So I did something unheard of," recalls Rosenthal. "I took the grant and the reviews, and I literally sent them to the National Institute on Aging," which agreed to support her research. Rosenthal began attending NIA workshops and "became totally hooked on the problem," she says. As she saw it, aging raised questions about "how the body maintains pattern--and then doesn't maintain it," a puzzle that she found as interesting as the mystery of how the body develops its patterns in the first place.

In the early '90s, another line of inquiry serendipitously dovetailed with her new interest in aging. Rosenthal's brother-in-law was diagnosed with type II diabetes, a disease marked by the body's unresponsiveness to insulin, which stimulates cells to absorb glucose. Rosenthal wondered whether it was possible to alleviate the illness by manipulating the hormone's production in muscle. At a friend's suggestion, she focused her efforts on IGF-1, a protein related to insulin that other studies had hinted could also improve glucose uptake; most IGF-1 that circulates in the blood is produced by the liver, but muscle cells make the substance too. Rosenthal's initial idea of a diabetes remedy ultimately led her to a different path. Working with colleagues at the University of Pennsylvania in Philadelphia, her lab at Massachusetts General created transgenic mice that overproduced a form of IGF-1 only in their skeletal muscles. These rodents, it turned out, packed more brawn and less fat and lived longer than their wild-type counterparts. Further studies in skeletal and heart muscle by Rosenthal's group have suggested that IGF-1 stimulates stem cells within muscle fibers to regenerate muscle tissue.

Stepping Up to a European Adventure

Rosenthal's career was flourishing at Harvard. By the late '90s, she had enough grant money, lab space, and complete independence, and her group was publishing key findings on muscle genetics. She was also serving as editor of the "Molecular Medicine" section in the New England Journal of Medicine. Yet after a few years at Massachusetts General, the shine of the place began to dull. Because of space constraints, she says, a number of her colleagues in the heart research center had left. And the director who hired her, Mark Fishman, had assumed the additional mantle of chief of cardiology at the hospital's main campus, so his attentions were divided. With her circle of friends and collaborators dwindling, Rosenthal found herself missing the collegial give-and-take she had known at NCI and Boston University. "I was spending more and more of my time setting up collaborations with people around the world, rather than on my back doorstep," she says. Moreover, her first marriage, a relationship of 15 years, was breaking up. "I was doing a lot of soul-searching about what I was doing with my life." She began considering other options.

So when EMBL's director-general, Kafatos, offered her the job at Monterotondo in late 2000, she said yes. "I've always been a bit of a reckless person, I guess. I make my decisions very quickly, and I also don't mind an adventure," she says. Colleagues who were skeptical about doing science in Italy didn't fully grasp that she would be working for EMBL, a premier scientific institute, at a research campus that just happened to be in the land of cappuccino and pasta, she says.

Rosenthal says that she finds EMBL's structure and accomplishments impressive. Headquartered in Heidelberg, Germany, the 29-year-old institute is funded by 15 European nations and Israel. There is no tenure system. The mission is to train young European researchers and send them back to their native countries with scientific know-how and international connections. So most investigators work at EMBL on one-time, 9-year contracts, during which they receive generous funding--an enormous relief from the constant pressure to secure grants that most researchers face, Rosenthal says. She herself holds a potentially open-ended appointment, working on a contract that can be renewed every 5 years.

At Monterotondo, a major focus of the EMBL program is to collect rodent strains in which scientists can activate specific genetic defects at any time during the animals' life. Such mice will help make the biology of aging more transparent, Rosenthal says. Right now the trouble with most genetic manipulations, she says, is that they exist in the genetically engineered animal from the minute it is conceived, so they have an effect throughout embryonic development and adult life. "We've got to be able to manipulate genes at a later stage, so that we can study their effect specifically on aging," she says.

Female Muscle Power

Rosenthal is the first American to head an EMBL research campus, and one of the first women--she was appointed at the same time that structural biologist Janet Thornton took over EMBL's European Bioinformatics Institute in Cambridge, U.K. Rosenthal's admirers attribute her success to a combination of intelligence, effervescent charm, and a feisty and optimistic resilience. "She's an energetic, positive person with a zest for life, and she's combined that with cutting-edge science," says Olson of the University of Texas Southwestern Medical Center in Dallas. "She's one of these people that lights up the room when she's around."

"Not only is Nadia a great scientist, but she has this tremendous skill to communicate and understand people of different cultures, and to energize people toward collaborative efforts," adds friend and stem cell researcher Helen Blau, director of the Baxter Laboratory in Genetic Pharmacology at the Stanford University School of Medicine in Palo Alto, California. Rosenthal's move from Harvard to Italy demonstrates a fearlessness with which she tackles life, says cell biologist Miranda Grounds, who studies muscle regeneration at the University of Western Australia in Perth, where Rosenthal also holds an honorary appointment as professor-at-large. "You have to have the courage of your convictions to do that," Grounds says.

Looking back on the road she's traveled, Rosenthal says that although she could have done without some of the negatives she encountered as a graduate student at Harvard, she received an "extraordinary education" there. "I don't think I could've toughed it out for the next 25 years if I hadn't been through that early experience." Science remains a challenging field for women, she says, but she believes that its rewards are worth the effort. "It's a great life. It's so much fun. I mean, discovery--it's the best high there is."

At the same time, having seen one marriage founder, Rosenthal candidly acknowledges that her personal relationships have had to take a back seat to her career. Three years ago she got remarried, to an English molecular biologist named Alan Sawyer, who she says accepts her obsession with work and is extremely supportive. "It's a very tough thing to find the right mix of woman scientist and partner. Some women have done it and are very happily married and have kids and still maintain a perfectly stellar career. But I think it's harder than it looks." And although there are moments when she regrets not having children, she says, "There's a freedom to my life that is just amazing. I feel that I can realize so many of my ideas and my dreams without really having to compromise anybody else's life."

Fantastical form. This color pencil drawing by Rosenthal graced a program book cover for a recent meeting on evolution and developmental biology at Cold Spring Harbor Laboratory. The illustration was inspired by an ancient statue of a gryphon that Rosenthal, a runner, jogs past every day in the Villa Borghese in Rome. [Credit: Nadia Rosenthal]

Artistic expression remains a part of those dreams. Rosenthal keeps her pencils and paints close by. The ability to think visually has been a plus, she says, because every developmental biologist must be able to imagine how a maturing organism looks in three dimensions and from a variety of perspectives. "One of the things I routinely do is draw the hearts of the organisms that I study, to understand better how they form."

She also creates artwork for scientific posters and conferences. She drew a mosaic of interlocking mice in the style of M. C. Escher that made it onto the cover of Nature Reviews Genetics in 2001. For a meeting last year about evolution and developmental biology at Cold Spring Harbor Laboratory in Long Island, New York, she drew a fantastical creature--part human, part bird--for the program book. She has also designed a silver award medal for the Australia and New Zealand Society for Cell and Developmental Biology that features a winged woman and a map of the two countries. "I was able to go over to the Perth mint and watch my coin being struck," she says. "I never expected in a million years to design a coin."

Between administrating, drawing, dreaming, and doing science, Rosenthal shows no sign of slowing down. And when asked if she ever will, she says, "I'll rest in the grave."

* Ingfei Chen is SAGE KE contributing editor in Santa Cruz, California, who would prefer to start resting now.