The Italian researcher faced prejudice and adversity as a woman and as a Jew, but went on to elucidate a growth factor essential to the survival of nerve cells
Sunday, December 30, 2012
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Editor's Note: Neurobiologist Rita Levi-Montalcini, a Nobel laureate in physiology or medicine in 1986, died December 30 at the age of 103. We are making this profile of her free online for the next 30 days. This story was originally published in the January 1993 issue of Scientific American.
As a feminist in a family with Victorian mores and as a Jew and free-thinker in Mussolini’s Italy, Rita Levi-Montalcini has encountered various forms of oppression many times in her life. Yet the neurobiologist, whose tenacity and preciseness are immediately apparent in her light, steel-blue eyes and elegant black-and-white attire, embraces the forces that shaped her. “If I had not been discriminated against or had not suffered persecution, I would never have received the Nobel Prize,” she declares.
Poised on the edge of a couch in her apartment in Rome that she shares with her twin sister, Paola, Levi- Montalcini recalls the long, determined struggle that culminated in joining the small group of women Nobelists in 1986. She won the prize for elucidating a substance essential to the survival of nerve cells. Her discovery of nerve growth factor led to a new understanding of the development and differentiation of the nervous system. Today it and other similar factors are the subject of intense investigation because of their potential to revive damaged neurons, especially those harmed in such diseases as Alzheimer’s.
The journey from Turin, where she was born in 1909, to this serene and impeccable Roman living room laden with plants and with the etchings and sculptures of Paola, a well-known artist, tested Levi-Montalcini's mettle from her earliest years. "It was a very patriarchal society, and I simply resented, from early childhood, that women were reared in such a way that everything was decided by the man, she proclaims. Initially, she wanted to be a philosopher but soon decided she was not logically minded enough. When her governess, to whom she was devoted, died of cancer, she chose to become a doctor. There only remained the small matter of getting her father, an engineer, to grant permission and of making up for the time she had lost in a girls’ high school, where graduation led to marriage, not to the university. That “annoyed me so much that I decided to never do as my mother did. And it was a very good decision—at that time, I could never have done anything in particular if I had married.” Levi-Montalcini pauses, leans forward and asks in- tensely, “Are you married? ” She sighs with relief at the answer. “Good,” she says, smiling.
After she received her father’s grudging consent, Levi-Montalcini studied for the entrance examination and then enrolled in the Turin School of Medicine at the age of 21. Drawn to a famous, eccentric teacher, Giuseppe Levi, she decided to become an intern at the Institute of Anatomy. There Levi-Montalcini became adept at histology, in particular at staining nerve cells.
Since Levi was curious about aspects of the nervous system, he assigned his student a Herculean labor: to figure out how the convolutions of the human brain are formed. In addition to the overwhelming undertaking of finding human fetuses in a country where abortion was illegal, “the assignment was an impossible task to give your student or an established scientist,” Levi-Montalcini explains, her voice hardening. “It was a really stupid question, which I couldn’t solve and no one could solve.”
She abandoned the project—after a series of unpleasant forays for subject matter—and with Levi’s permission began to study the development of the nervous system in chick embryos. Several years later she was forced to stop that work as well. Mussolini had declared his dictatorship by 1925 and since then anti-Semitism had grown in Italy. By 1936, hostility was openly apparent, and in 1939, Levi-Montalcini withdrew from the university, worried about the safety of her non-Jewish colleagues who would be taking a risk by letting her study.
Levi-Montalcini accepted an invitation to conduct her research at a neurological institute in Belgium. But, fearing for her family, she soon returned to Turin—just before Mussolini and Hitler forged their alliance. Undeterred, Levi-Montalcini continued her research: “I immediately found a way to establish a laboratory in my bedroom.” In the years that followed, bombs fell repeatedly, and again and again she would lug her microscope and slides to safety in the basement.
In spite of the hardship—or perhaps, as Levi-Montalcini sees it, because of the adversity—it was during this time that she laid the groundwork for her later investigation of nerve growth factor. “You never know what is good, what is bad in life,” she muses. “I mean, in my case, it was my good chance.” Levi-Montalcini and her family left Turin in 1942 for the surrounding hills and successfully survived the war in hiding. By convincing farmers that she needed eggs for her children (whom she did not have), Levi-Montalcini studied how embryonic nerve tissue differentiates into specialized types. The prevailing theory, developed by renowned biologist Viktor Hamburger of Washington University, held that the differentiation, or specialization, of nerve cells depends in large part on their destination. In his experiments, Hamburger removed developing limbs in chick embryos to see how such excision would affect the later growth and differentiation of the nerve cells destined for that region of the embryo.
Hamburger observed that the centers of embryonic nerve cells near and in the developing spinal column—where the cells start their journey out to other tissues—were much smaller when he excised the limb buds. He suggested that some inductive or organizing factor, probably contained in the limb, could no longer call out to the nerve cells. Therefore, they neither specialized nor grew away from the developing spinal cord into the region of the absent limb.
After conducting experiments directed at the same question, Levi-Montalcini reached a different conclusion. She found that fewer nerve cells grew into the area where the limb bud had been eliminated, but she proposed that some kind of nutrient, important for the survival of nerve cells and normally produced by the limb, was missing. Her theory differed from Hamburger’s view because Levi-Montalcini proposed that nerve cell differentiation did take place despite the removal of the limb but that the cells soon died because they did not receive some sustaining, trophic factor. The limb did not contribute to differentiation, that is, it did not contain an organizing factor; rather it produced something that nourished already specialized nerve cells.
A paper of hers on this topic was published in a Belgian journal and was read by Hamburger, who invited her to St. Louis in 1946. Hamburger wanted to work with Levi-Montalcini on the problem of nerve cell differentiation— and, indeed, later came to agree with her interpretation. Although she initially accepted a semester-long research position at Washington, Levi-Montalcini remained until 1961. She is now professor emeritus at Washington but spends most of her time in her native country.
Levi-Montalcini recalls being unsure of the future of her research after she arrived in the U.S. One afternoon, a series of observations, as well as the presentation of a challenge, gave her a renewed sense of purpose. At that time, neurobiologists thought differences in the number and function of various nerve cells were mostly the consequence of proliferative processes.
But Levi-Montalcini was about to discover that the developing nervous system, at least in parts, uses a strategy different from the one previously assumed. She had prepared a series of tissue slides of chick embryo spinal cords in different stages of development. By looking at the succession of slides, she was able to observe the migration of nerve cells early in development to their final positions alongside the spinal column. There, for the first time, she saw the later elimination, or pruning back, of some of them. “I put on a Bach cantata because I was so terribly happy. I had realized that there was still so much to be discovered,” says Levi-Montalcini, her delight vividly clear.
Over the next several years, Levi-Montalcini focused on searching for the mysterious trophic factor that she had intuited during the war. A former student of Hamburger’s had fortuitously noticed that a certain mouse tumor cell line— called sarcoma 180—caused more nerve cells to grow. When Levi-Montalcini incorporated the tumor cells into developing chicks, she observed the same effect. Something in the tumor caused the differentiation of the nerve cells to accelerate; it also caused the creation of excessive numbers of nerve fibers.
Levi-Montalcini started trying to isolate the trophic factor and began to collaborate with biochemist Stanley Cohen, then at Washington and now at the Vanderbilt University School of Medicine. They found that the partially purified factor contained both protein and nucleic acid. By adding enzymes from snake venom—which breaks down these compounds—in hopes of determining which component contained the biological activity, the two discovered that the venom itself contained the factor.
This finding (described in detail in her autobiography, In Praise of Imperfection) led to the realization that nerve growth factor is produced in salivary glands in mice, providing a new, easy source for studies of the material. By designing an antiserum, Levi-Montalcini and Cohen were able to chart the role of the factor. It became clear that it is essential to the differentiation and health of nerve cells.
In 1986 Levi-Montalcini and Cohen shared the Nobel Prize for this achievement. When the phone rang in Rome with the news, she was pages from the end of Agatha Christie’s Evil under the Sun. “At the moment that I was finding out about the criminal, they told me that I was awarded the Nobel,” she laughs, getting up to retrieve the book from the hallway. She points to a hand- written note on the second-to-last page—befitting a neuroscientist, her edition has a skull on the cover—where she had marked “call from Stockholm” and the time. “So I was very happy about it, but I wanted much more to know the end of the story,” she admits.
Although she says her popularity interferes with her life, Levi-Montalcini has used the Nobel to extend her work into areas that concern her. She is president of the Italian Multiple Sclerosis Association and is a member of the Pontifical Academy of Sciences; she was the first woman to be elected to the academy. “I can do things that are very, very important, which I would never have been able to do if I did not receive it,” she says. “It has given me the possibility of helping a lot of people.” And she helps whomever she can. The phone rings incessantly in her apartment. “People ask for medical help,” she explains, after answering each call and graciously talking with the parents or other relatives of someone ill. “But sometimes there is nothing to do.”
In addition, Levi-Montalcini and her sister recently started their own project: a foundation that will provide mentors, counseling and grants to teenagers deciding what field, whether it be art or science, to enter. For several hours every week, she receives young students in her laboratory at the Institute of Neurobiology at the National Research Council in Rome and talks with them about their interests and her experiments. “The only way to help is to give young people a chance for the future. Because we cannot fight the Mafia, we cannot fight corruption without giving an alternative to young people,” she says.
Levi-Montalcini’s research at the institute, which she founded in the 1960s, has also taken a new turn. She is studying the role of nerve growth factor in the immune and endocrine systems. “The neotrophic factor was just the tip of the iceberg,” she notes. “So even now I am doing something entirely different. Just in the same spirit as when I was a young person. And this is very pleasing to me,” she says, laughing. “I mean, at my old age, I could have no more capacity. And I believe I still have plenty.”
Taken From SciAm
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