The human body begins as a single cell that proliferates into a few identical daughter cells which ultimately grow into billions of specialized body cells. Scientists and physicians have long recognized the pattern of this process, called differentiation, but how it works was a mystery.
Then in the early 1950s, an Italian developmental biologist transplanted to the United States, Dr. Rita Levi-Montalcini, provided the first clue. Levi-Montalcini and her colleague, American biochemist Stanley Cohen, identified and ultimately isolated and purified nerve growth factor, a hormone that tells growing nerve cells where to go.
The discovery was a seminal development in the understanding of the mechanisms that regulate cell and organ growth and established an entirely new field of biological study. It also won the pair the 1986 Nobel Prize in Physiology or Medicine, making Levi-Montalcini only the fourth woman to receive that particular honor.
Levi-Montalcini died at her home in Rome on Sunday at the age of 103. Her death was announced by Rome's mayor, Gianni Alemanno, who called it "a great loss for all of humanity." In a statement, he said she represented "civic conscience, culture and the spirit of research of our time."
The discovery of nerve growth factor (NGF) and others that came after it — epidermal growth factor, insulin-like growth factor and a host of others — illuminated many disease processes, including cancer, Alzheimer's disease and developmental malformations. And as researchers learn how to produce the hormones in bulk, the chemicals promise new approaches to therapy.
She was born April 22, 1909, in Turin, one of four children of Adamo Levi and Adele Montalcini. Her father was an engineer and a strict Victorian who blocked his daughters from college because he thought it would interfere with their lives as wives and mothers. Because of Levi's domination of both his wife, who was a painter, and his daughters, she vowed that she would remain unmarried and childless, a vow she kept.
When Levi-Montalcini was 20, her beloved governess was stricken with cancer and that inspired her to stand up to her father and become a physician. With his eventual blessing, she graduated from the University of Turin medical school in 1936 with the highest honors. At the university, she was mentored by histologist Giuseppe Levi (no relation), who also mentored Nobel laureates Salvador Luria and Renato Dulbecco.
She enrolled in a specialization in neurology, but was unable to continue when Italian dictator Benito Mussolini banned Jews from all professional careers. After a brief sojourn at a neurological institute in Brussels — ended prematurely by the imminent German invasion — she returned to Turin and established a laboratory in the bedroom of her parents' home, where she studied the development of chicken eggs. Her first and only assistant was Giuseppe Levi, who also had escaped from Belgium.
Bombing of Turin by the Allies forced her to move to a country retreat, but when the Germans invaded Italy in 1943, her family fled to Florence, where they changed their names and assisted partisans in the war effort. After the Americans liberated Florence, she became a physician at refugee camps.
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In 1947, biochemist Viktor Hamburger noticed one of her papers detailing her studies with eggs and invited her to join him at Washington University in St. Louis. She had intended to come for a year or less, but ended up staying three decades and gaining dual citizenship.
By 1952, Levi-Montalcini had shown that transplanting mouse tumors into chicken embryos sharply accelerated the growth of the embryos' nervous system. This occurred even when the tumors were not in direct contact with the embryos, indicating that they were secreting some substance that promoted nerve growth.
She developed a biological assay that was critical in isolating the factor, which proved extremely potent. A single ganglion cell from a chick embryo would sprout nerve fibers resembling the rays of the sun when the factor was present.
The following year, Cohen joined the lab and, within three years, they had narrowed the candidates down to a small mixture of proteins and nucleic acids. Trying to decide which type of molecule was the growth factor, Cohen added snake venom to the mixture, which should have destroyed any DNA present.
To the pair's surprise, however, the new mixture was more active than their experimental brew: The snake venom contained high levels of NGF. A systematic search led them to another source of the hormone, the salivary glands of male mice. These two new sources gave them enough NGF to finally isolate it in its pure form.
They found that NGF was a protein composed of 118 amino acids. Two of these proteins joined together to form the active molecule. Released from a cell, NGF causes other nerve cells to sprout neurons to link to the original cell.
In subsequent years, the team found other growth-promoting hormones, greatly expanding the field.
In 1969, Levi-Montalcini established the Institute of Cell Biology of the Italian National Research Council in Rome, spending half the year there and half in St. Louis. She returned to Rome full time in 1977. In 2004, she established the European Brain Research Institute, also in Rome.
Despite the fact that she was Jewish and liberal, she was the first woman admitted to the Pontifical Academy of Sciences, which advises the Vatican. She was appointed an Italian senator for life in 2001 and remained active in politics.
She also established a foundation to assist African women in attending universities. By her 100th birthday, the fund had helped more than 7,000, she said.
Although her vision and hearing were impaired with age, she continued working well into her 100s. In an interview three years ago, she argued that, "At 100, I have a mind that is superior — thanks to experience — than when I was 20." Life, she said, "has not treated me badly. I am a woman with no regrets — and, I think, without any sins on my conscience."