Chronic pain affects more patients than cancer, cardiovascular disease (CVD) and diabetes combined. Yet unlike these conditions — which typically emerge later in life—chronic pain can be related to a fundamental protein which is found at birth. Essential for the growth, development, and survival of certain neurons, that protein is called Nerve Growth Factor (NGF), and developing drugs to treat some chronic pain conditions requires knowledge and understanding of NGF. Yet, this wasn’t possible till the 1950s when Rita Levi-Montalcini, MD, discovered its existence. For that, she and her colleague, Dr. Stanley Cohen, won the Nobel Prize in Physiology or Medicine in 1986.
A primer on NGF
NGF is a protein needed to promote the growth and survival of peripheral sensory and sympathetic nerve cells. The peripheral sensory nerves, which lie outside the brain and spinal cord (the central nervous system), allow us to transmit sight, hearing, touch, taste, and odor information to the brain for processing – thereby enabling our experiencing sensations associated with those faculties. The sympathetic nervous system controls automatic responses, such as speeding up the heart rate to deliver more blood to areas requiring oxygen, regulating blood pressure, digestion, urination and sweating, enabling the flight or fight reaction, and producing the “stress response.”
Initially, NGF was thought to modulate only childhood nerve functions, but now we know NGF helps modulate the sensation of pain (nociception) in adulthood. Increased levels of NGF are found in chronic pain associated with conditions including osteoarthritis, rheumatoid arthritis, fibromyalgia, low back pain, and intestinal cystitis, to name some. In addition to fostering survival of nociceptive (pain sensation) neurons, NGF’s impact on pain comes from its immune function as an inflammatory mediator. Nevertheless, the importance of NGF only became apparent in the 1970s, along with its involvement in neurodegenerative diseases.
“NGF is one of many inflammatory mediators that facilitate pain sensitization. It is released from mast cells along with other pro-inflammatory cytokines such as histamine and interleukins.”
— Dr. Robert Bolash, pain management specialist, Cleveland Clinic
Thanks to this discovery, a new generation of pain-reduction therapies is on the horizon; novel pain therapeutics targeting the NGF pathway, including monoclonal antibodies, are currently in early discovery or preclinical stages. Beyond pain management, NGF’s therapeutic potential has also been demonstrated in treating human cutaneous and corneal ulcers, pressure sores, glaucoma, maculopathy, and retinitis pigmentosa. Wound healing, encephalomyelitis, heart failure, and glaucoma are just some of the conditions that may be amenable to NGF therapies in the future.
In the Beginning…
Rita Levi was born in 1909 to a middle-class Jewish family in Turin, Italy, an auspicious enough beginning. However, her father, an electrical engineer, was against advanced education for women. While his sisters were highly educated, Adamo Levi blamed the deterioration of their marriages on their education and forbade his daughters from continuing their studies after high school. Mr. Levi’s views did not affect Rita’s highly talented and artistic twin sister, Paolo, who was able to achieve widespread recognition for her talents as an artist without a higher degree, nor on her older brother who became a renowned architect.
But for Rita, this edict chafed, primarily because the life of a housewife did not suit her. Initially, she wanted to study literature. But like other great women scientists on our list, the death of a loved one from cancer ignited her interest in medicine. At 20 years old, she confronted her father and received his permission to pursue a medical degree, making up the deficits in her education in just eight months before enrolling in the University of Turin’s medical school.
“At 20, I realised that I could not possibly adjust to a feminine role as conceived by my father and asked him permission to engage in a professional career.”
— Rita Levi Montalcini
The Hero’s Journey:
Upon graduating in 1936 with high honors, in deference to her mother’s influence on her life, Rita appended her mother’s maiden name to Levi and became Levi-Montalcini . Realizing she wasn’t comfortable with the emotional demands of a practicing physician, Dr. Levi-Montalcini devoted her efforts to research, first becoming a research associate to one of her professors, Dr. Guiseppi Levi (no relation).
She performed admirably and contentedly in that role for two years — until Mussolini’s Race Laws forbade non-Aryans from having a professional or academic career forcing her to flee to Brussels. There she worked at a research facility for a short time before the onslaught of Hitler’s troops compelled her return to Turin in 1940.
Locked out of the University’s laboratory, she set up her own lab — in her bedroom. In an odd turn of events, she was now assisted by her former professor, Dr. Guiseppe Levi, whose expertise offset his clunky, elephant-like anatomy which did not lend itself to maneuvering with delicate instruments in a small bedroom. There, the two experimented on chick embryos to discern how nerve fibers grew until the Nazis overran Italy two years later. To augment their food rations, she used the discarded embryos to make omelets for her family, much to her brother’s disgust.
“I should thank Mussolini for having declared me to be of an inferior race. This led me to the joy of working, not any more unfortunately in university institutes, but in a bedroom.”
Along with her family, Rita fled to the northern Piedmonte region, and then to Florence. In 1943, no longer able to maintain her bedroom laboratory and forced to live “underground,” Rita offered her medical services to the Allied forces, working as a physician in a refugee camp. Finally, the war ended and she was allowed to return to Turin University where she resumed her research and publication.
America Beckons
In 1947, Rita received an invitation from professor Viktor Hamburger – whose 1934 article first inspired her research – to collaborate with him at the Washington University in St. Louis and resume her work on chick embryos.
Based on his experiments with motor neurons, Hamburger had postulated that nerve generation and survival were dependent on the existence of a target tissue, for example, a limb bud. Rita disagreed. Working with sensory neurons, her observations, and large doses of intuition, she predicted that even in the absence of a target, nerve survival depended on a growth-promoting substance.
Her initial plan was to remain in St. Louis for less than a year, but extraordinary research results delayed her return to Italy. And so she remained in St. Louis until her retirement in 1977. Along the way she spent a stint in Rio, Brazil, where she learned sophisticated laboratory techniques from another great woman of science, Dr. Hertha Meyer.
By 1962, family-longing drew her back to Italy. Not willing to abandon her stellar progress in Hamburger’s St. Louis lab, she returned to Rome for several months a year, establishing the European Brain Research Institute (EBRI) in Rome in 2002 and directing the Institute of Cell Biology of the Italian National Council of Research.
Rita’s work on NGF was received by the scientific community with suspicion and doubts about its relevance and applicability. Her intuitive methodology and imaginative leaps in reasoning, not unlike Nobelist Barbara McClintock’s approach, was also severely criticized — but the approach worked, although it took isolation of the substance by Dr. Stanley Cohen and later discoveries in neurodegenerative diseases for the discovery of NGF to receive the recognition it merited.
More than just a stylish lady in a lab coat and heels
In 2001, Dr. Levi-Montalcini was made Senator for Life of the Italian Parliament, never missing a session until her death. While often finding the sessions stressful, she used her position to advocate for policies fostering science and education, condemning any form of prejudice.
Dr. Levi-Montalcini’s impact didn’t end there. She was an avid mentor of women in science, especially those from under-privileged backgrounds, with whom she felt an affinity. Together with her twin sister, she funded the Rita Levi-Montalcini Onlus Foundation to provide scholarships for young African women to pursue careers in science, granting fellowships particularly in medicine and nursing.
After a long and illustrious career spanning almost nine decades and three continents, Levi-Montalcini passed away in 2012 at aged 103 in her native Turin.
Unlike male scientists whose creativity, like Einstein’s musical pursuits or Lederman’s artistic talents, was often celebrated, women like Rita Levi-Montalcini faced criticism for their artistic expression. Refusing to be confined, she adorned herself with self-designed jewelry and clothing, maintaining a signature elegance. "With a beautifully styled coif ... she wore high heels with her lab coat and wielded delicate spatulas with exquisitely manicured hands,” embodying a seamless blend of creativity and scientific rigor that challenged conventional expectations.
Even though women were chastised for this self-expression, Levi-Montalcini proved that brilliance needs neither permission nor convention. From a bedroom lab under fascist rule to the Nobel stage and the Italian Senate, she redefined not only neuroscience — but the very image of what a scientist could look like and could accomplish in translating science to policy.
Further reading:
Francesca Valente, Rita Levi-Montalcini, Pioneer & Ambassador of Science
Catherine Whitlock and Rhodori Evans, 10 Women who changed Science and the World
