Italian neuroscience pioneer Rita Levi-Montalcini died last week in her home in Rome. She was 103 and had been working right to the end. Her death was announced by Gianni Alemanno, the mayor of Rome, who called it "a great loss for all of humanity." He said Levi-Montalcini represented "civic conscience, culture and the spirit of research of our time."
With Stanley Cohen, Levi-Montalcini was awarded the Nobel Prize in Physiology or Medicine in 1986 for the discovery of nerve growth factor (NGF). Before we discuss why and how NGF is important in the repair of the brain or spinal cord, consider the fascinating biography of Levi-Montalcini, beset by patriarchal discouragement, anti-Semitism, and war, but fortified with passion and uncommon mental clarity (courtesy the Los Angeles Times obituary):
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.
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.
While at Wash U, Levi-Montalcini continued her chick embryo work, observing that sensory nerve fibers will grow rapidly and sprout new axons in the presence of specific mouse tumor cells.
Moses Chao, Ph.D., professor at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, and former head of the Reeve Foundation Science Advisory Council,
interviewed Levi-Montalcini shortly before her 100th birthday. In his introduction, he describes her work:
The theory she developed was quite elegant and simple. Competition of nerve cells early in development for limited amounts of growth factors produces winners and losers. The winners are nerve cells that made the correct connections with their targets, and the losers undergo death, which explains the massive amount of programmed cell death that occurs in the peripheral nervous system.
Chao, who also studies growth factors, has a deep appreciation for Levi-Montalcini’s contribution to science:
One of her initial observations was that if you implant specific mouse tumor cells on a chick embryo, sensory neurons will grow rapidly and sprout new axons which will innervate the tumor cells, again confirming that certain target tissues can promote nerve growth in embryonic tissues. The question was how did the target tissues do this? The key experiment came when she and her colleagues grew on one end of a cell culture dish some of these mouse tumor cells, and on the other a bit of neural tissue known as a sensory ganglion. After a few days, she observed that the neurons in the sensory ganglia grew a bunch of new axons, and these axons seemed to be oriented toward the tumor cells. As if they were being attracted. This told her that the tumor cells were actually releasing some soluble factor into the growth media. The factor promoted growth of nerve cells and helped them live longer in a culture dish. This factor was later isolated by biochemist Stanley Cohen and shown to be a protein which they dubbed, imaginatively, nerve growth factor.
Nerve growth factor is a soluble protein secreted by various tissues in the body that promotes the growth of nerve cell processes and survival of neurons. NGF was the first discovery among several molecules known as neurotrophins. These molecules activate protein receptors in target cells (tyrosine receptor kinases) and are crucial to the initial wiring of the developing nervous system.
In adults, growth factors are important for learning, memory, and nerve regeneration. Early gene therapy experiments (1994) from Mark Tuszynski and his Ph.D. advisor Rusty Gage at the University of California, San Diego, showed a “huge” amount of nerve growth in paralyzed animals treated with NGF. They also engineered a different growth factor, NT-3 and were able to show partial limb recovery.
In 2005 Tuszynski also used NGF in a
Phase I trial for Alzheimer’s disease. Results were encouraging.
In spinal cord injury, Schwann cell transplants (Miami Project clinical trial) do not replace damaged cells but are believed to release growth promoting factors to nurture surviving nerves. There are numerous clinical trials listed at www.clinicaltrials.gov for a variety of conditions, including brain injury, diabetes, ALS, depression, Parkinson’s, obesity, etc.
Levi-Montalcini has continued her research as head of the Institute of Cell Biology of the Italian National Research Council in Rome, which she founded. Her legacy extends beyond science. She was named a senator for life in the Italian Senate and actively promotes inclusion of women in scientific research.
How did she live so long? She doesn’t sleep much, never married and eats as little as possible. She told Chao:
I do not know if this is [why] I live so long, but at night I do not sleep but I think. Because there’s wasting time in sleeping. All the night I think, and in the morning I have new ideas, but this is because I am totally indifferent to food and indifferent to sleep, never cared. I believe we give too much importance to sleep and food. Normally, I don’t sleep in the night. I take half an hour, not every day, but sometimes in the afternoon, that’s all. I’ve no interest in sleeping. It is wasting time.
Two days after her 103rd birthday last April, Levi-Montalcini, posted a note on
Facebook saying it was important never to give up on life or fall into mediocrity and passive resignation.
“I’ve lost a bit of sight, and a lot of hearing. At conferences I don’t see the projections and I don’t feel good. But I think more now than I did when I was 20. The body does what it wants. I am not the body, I am the mind,” she said.
Once asked to disclose the secret behind her long and healthy life, Montalcini said: “Be happy to be alive and to be of service to others.”
“I am not in the least frightened of dying, it will only affect this very small body that I have lived in. It is not important when I die. The important thing is to have lived with serenity using the rational left-hand side of one’s brain, and not the right side, the instinctive side, which leads to misery and tragedy.”
