Faced With Fascist Rule and Anti-Semitism, a Titan of Neuroscience Emerges

If I had not been discriminated against or had not suffered persecution, I would never have received the Nobel Prize. —  Rita Levi-Montalcini

During the early days of World War II, in a small apartment in Turin, Italy, Rita Levi-Montalcini set up a laboratory in her bedroom.

Benito Mussolini was in power, and the fascist leader's recently-enacted Race Laws — or the Leggi razziali — limited the rights of Italy's Jewish citizens, Levi-Montalcini included. A budding physician, Rita had graduated from the University of Turin's medical school in 1936. She later took a position at her alma mater as a research assistant, studying the development of the nervous system. Yet the anti-Jewish sentiment in Italy at the time weighed heavy. Not wanting to jeopardize the reputation of her colleagues she made the tough decision to resign and set up a clandestine lab of her own.

When Allied bombing in Turin picked up, she moved with her family to the countryside, bringing her microscopes and microtome with her. Supplied with fertilized chicken embryos from nearby farms, she began studying how neurons migrate during development to form the nervous system, and would go on to win the Nobel Prize in Medicine and Physiology in 1986 for her work on the developmental role of nerve growth factor (NGF) and other neurotrophins, the proteins that support and drive neuronal survival, development, and function.

Levi-Montalcini's discoveries would contribute to the understanding of neurogenesis, neoplasias, and neurotrophic treatments for neurodegenerative disease. Perhaps more striking is that she managed to overcome near insurmountable sociopolitical odds to build a prestigious career as a world-renowned neuroscientist, contributing to our understanding of how our nervous system comes to be.

But it all began in that bare-bones bedroom in Turin.

An Intellectual Family

Rita Levi-Montalcini was born April 22, 1909, along with her twin sister, Paola. Their mother, Adele Montalcini, was a talented painter; their father, Adamo Levi, an engineer and mathematician with an authoritarian mindset, believing, like most men of the era, that girls should be raised primarily to become good wives and mothers. Yet Adamo had sisters with doctoral degrees and an older daughter doing exceptionally well in school. Deep down he seemed to realize that women could excel as well as men.

As a child, Rita admired the nurses of World War I and often played hospital. Guided by her nanny on rainy days, she would 'operate' on her dolls, sewing their injuries with thread, as if suturing wounds. When Rita was 20, the nanny died of gastrointestinal cancer. Distraught, she asked her father to support her in studying medicine.

Adamo reluctantly agreed.

Despite holding traditional views on gender roles, Rita's father was quite liberal when it came to religion. He was of Sephardic Jewish heritage like his wife, yet a proud freethinker — an attitude that was increasingly common among Ashkenazi Jews at the time, but generally not Sephardim. Insisting that his four children grow to adulthood before choosing a religion — or before choosing no religion at all — Adamo's independent nature may have influenced Rita to contemplate science and a career in biomedical research.  

But her coming of age at a time when the lexicon and law in Mussolini's Italy distinguished Jews as a race separate from the "Italian race" foreshadows the view that Rita would later embrace around modern genetics: that "race" is a meaningless term for distinguishing groups of humans.

Over her career, Rita would feel the effects of anti-semitism and gender bias in science and medicine, but in interviews later in life she would view gender bias as an ever-present problem compared with anti-semitism which, at least in her case, was an issue only during the war. In one interview, she remarked specifically that, during her youth, science had been extremely challenging for women, whose main responsibilities were supposed to be those of wives and mothers.

Medical School and Beyond

Though Italy under Mussolini was aligned with Nazi Germany until 1943, Jews generally were spared physical danger. But they were affected in many other ways. By October, 1938 — two years after she'd graduated from medical school — Mussolini's Race Laws had been enacted and the Levi-Montalcini family had to maintain a very low profile.

Initially, Levi-Montalcini persisted with research that she had begun as a medical student under the mentorship of Giuseppe Levi (no relation to Rita), a histology professor at the University of Turin. Assigned to help Giuseppe Levi understand the origins of cerebral convolutions, Rita worked initially with small rodents, but then turned to dissecting aborted human fetuses, which were hard to obtain at the time given that abortion was illegal in 1930s Italy.

Italian scientist Rita Levi-Montalcini wearing a white gown sitting and holding a mouse's tail.

Soon, though, her research led her to work with chick embryos; and by 1938 Rita had become fascinated with the phenomenon of neurogenesis. At the time, it was known that axons grow and migrate distally from the spinal column to their final destinations in limbs, organs, and tissues. But the mechanisms by which neurons proliferated, differentiated, and navigated to their target locations — and the means by which the nervous system pruned itself of unneeded neurons — were beckoning mysteries.

Rita was mostly able to work out of the university lab without raising red flags. But with the rise in anti-semitism she was concerned about endangering her non-Jewish colleagues. With Austria, Italy's northeastern neighbor, succumbing to the Anschluss in March 1938, and Czechoslovakia invaded several months later, it appeared her situation could only get worse. In 1939, Levi-Montalcini accepted an invitation to join a neurological institute in Brussels, Belgium, where Jews, at that moment, still had more freedom than they had in Italy. This would of course change in 1940 with the onset of the war, but prior to Germany's invasion of Belgium, Levi-Montalcini boarded a train back to safety in Turin.

Since working at the university was no longer an option, Rita did the next best thing. Convincing her parents to purchase microscopes, incubator parts, and other equipment, Levi-Montalcini set out to transform her bedroom into a secret research lab. Being an expert in the silver nitrate staining of neurons —a technique invented by Rita's compatriot and neuroscience pioneer Camillo Golgi (1843-1926), but perfected by his Spanish rival, Santiago Ramón y Cajal (1852-1934) — Rita was inspired by a makeshift lab that Ramón y Cajal had cobbled together in Valencia.

As so many of us are doing at the moment as the COVID-19 pandemic surges on, Levi-Montalcini made the best of working from home. Montalcini observed that even in a mutate chicken embryo without limb buds, a normal number of neuronal cells would migrate to the absent wing, only to die when they failed to make any connections.

Based on this, she hypothesized the existence of a factor that enabled neurons to grow, and published her findings and ideas in widely-read scientific journals. In St. Louis, Washington University embryologist Viktor Hamburger was intrigued. He was one of only a handful of researchers around the world already studying factors that promoted cellular growth.

In the summer of 1943, the Allies landed in Sicily, then took southern Italy as Mussolini's regime collapsed. Under a new government, Italy joined the Allies, so Hitler advanced to conquer northern Italy, prompting the Levi-Montalcini family to leave Turin and make way for the Allied-controlled south. Unable to continue her research, but having a medical degree, Rita put her microscopes away and dusted off her stethoscope, joining the Red Cross to work clinically for the remainder of the war.

Off to St. Louis

Not long after the war, Rita was contacted by Hamburger, who offered her a 7-month rotation at Washington University. That 7 months would become 30 years. During her tenure in St. Louis, Levi-Montalcini would help pioneer the  study of neurotrophic factors, known as neurotrophins, beginning with the growth factor that she would name NGF. Armed with her expertise in neuroembryology and Ramón y Cajal's perfected Golgi staining method, Levi-Montalcini was poised to make St. Louis the nerve center (pun intended) for neurotrophins.

Rita's team at Washington University went on to partner with biochemist Stanley Cohen, who helped them determine the molecular structure of NGF; in 1986 he would share the Nobel Prize with Levi-Montalcini for this work.

As with many biological agents discovered in the early and mid-20th century, an initial question that had to be answered was whether the agent was a protein or a nucleic acid. To find out, Cohen used snake venom, as it contains phosphodiesterase, an enzyme that destroys nucleic acids. If Rita's unknown substance was a protein, she and Stanley hypothesized that the snake venom would not reduce its activity, but if the substance was a nucleic acid, snake venom should eliminate or decrease its activity.

As it turned out, there was a third possibility. Snake venom actually increased nerve growth activity compared with control samples. The only possible explanation was that the venom itself contained the same growth substance, or something like it. Trying the same experiment with other venoms and other biological extracts, Levi-Montalcini and Cohen found that NGF and variations of it were present in various species and tissues.

Rita Levi-Montalcini (along with Dr Stanley Cohen) won the Nobel Prize in Medicine and Physiology for her work on the developmental role of nerve growth factor and other neurotrophins.

This revelation opened a plethora of possibilities in terms of how neurotrophins and other factors secreted by cells could micromanage development; how growth factors gone awry could cause abnormal development; and how deficiencies of growth factors could hasten tissue degeneration. Their work further supported the prospect of utilizing growth factors to mitigate or even reverse degenerative disease processes. Today, efforts are underway to treat Alzheimer's disease with NGF and other neurotrophins, and neurotrophin gene therapy is being explored to restore cochlear neurons in hearing loss.

A range of discoveries have since revealed that effects of neurotrophins and their inhibition control nervous system development and the pruning of unneeded cells. This would have sounded like science fiction even as late as the 1970s, when Rita accepted a new faculty position in her native Italy and started living and working on both sides of the Atlantic.

Levi-Montalcini's 1986 Nobel Prize was far from the end of her career. She continued researching in the US and Italy right up until her death. In her later decades, she was appointed a Senator for life by the Italian government and worked encouraging girls and young women to consider scientific careers, creating (with her sister Paola), a foundation to fund scholarships for women in Africa, the Levi-Montalcini Onlus Foundation. Just months after publishing that final paper, Rita Levi-Montalcini died peacefully in her sleep on December 30, 2012, four months shy of her 104th birthday.

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Cite this: Faced With Fascist Rule and Anti-Semitism, a Titan of Neuroscience Emerges - Medscape - Oct 28, 2020.