by Diana Kwon
What do nerves need in order to grow? That question first caught Rita Levi-Montalcini’s attention in the 1930s, when she came across a recent paper by embryologist Viktor Hamburger. After observing that clipping the wing bud off chicken embryos stunted the growth of spinal nerves and ganglia on the side of the body with the excision, Hamburger reported that signals from the limb drove the growth and differentiation of immature cells in the central nervous system. Levi-Montalcini was intrigued. But after repeating the embryo experiments and finding that the chick’s nerve cells continued to develop after amputation and died later—just before reaching their target tissue—she came to a different conclusion. Rather than failing to initiate nerve growth, she hypothesized, the animals were unable to sustain the growing cells, causing a degenerative process that limited their proliferation.
Levi-Montalcini began these experiments at the University of Turin in Italy, but as a Jewish scientist, she was forced to leave in 1938 when Mussolini’s Fascist government made it illegal for her to work at state universities. She continued the work from a secret, makeshift laboratory in her bedroom until the end of World War II.
VENOMOUS GROWTH: Rita Levi-Montalcini and Stanley Cohen found that when nerve tissue from chicken embryos is cultured alongside snake venom, a rich source of nerve growth factor (NGF), it grows a dense halo of nerve fibers (right). Without NGF (left), fewer nerve fibers develop, and those that do grow are smaller. PNAS, 42:571–74, 1956
Levi-Montalcini sent reports to her former advisor, histologist Giuseppe Levi (no relation to Levi-Montalcini), then in Belgium, who published their coauthored manuscripts in academic journals. In 1946, Hamburger invited Levi-Montalcini to his lab at Washington University in St. Louis. Together, they found that many nerve cells die during normal development, and that limb amputations heighten this loss. Soon after, Levi-Montalcini followed up on the findings of Hamburger’s former graduate student Elmer Bueker, who had observed that, like the developing limb, a rapidly growing malignant tumor could also promote the growth of nerve cells in chicken embryos. Levi-Montalcini transplanted tumors onto the membrane around an embryo, where they were only connected to the developing animal by a common blood supply, and demonstrated that the tumors could still encourage neural growth. It seemed there was a diffusible agent that was influencing nervous system development.
In the early 1950s, Levi-Montalcini began collaborating with biochemist Stanley Cohen, who had just joined Hamburger’s lab. The pair isolated and characterized the mystery molecule, nerve growth factor (NGF), which turned out to be crucial for the development and survival of cells in the nervous system.Cohen later identified another factor, epidermal growth factor (EGF), which stimulates the growth of epithelial cells. And in 1986, Levi-Montalcini and Cohen shared the Nobel Prize in Physiology or Medicine for their discoveries of NGF and EGF, respectively. The discovery of these first growth factors was a “breakthrough in the field of extracellular messengers,” a category that also includes vitamins and hormones, says Pietro Calissano, a neuroscientist and vice president of the European Brain Research Institute in Italy, which Levi-Montalcini founded. “[NGF and EGF] brought to light the existence of an entirely new category of diffusible substances.”
Following the discovery of NGF, Levi-Montalcini spent much of the rest of her career investigating the role of the growth factor in the developing nervous system. Before passing away in 2012 at the age of 103, she also penned several books and set up a foundation to provide guidance and financial support to young students seeking higher education. Calissano, who worked with Levi-Montalcini for more than 40 years, remembers her as “a brilliant scientist and charming woman who liked to approach research with imagination.”