Rita Levi-Montalcini

Professor Rita Levi-Montalcini is one of the most respected and admired figure in Neurosciences of the 20^th century. She has in many respects dominated this field of science following her seminal discovery of the first of what was to become a large family of factors essential for the development of the brain and all elements of the nervous system. Her discovery of the Nerve Growth Factor has opened up a huge area of research into all aspects of normal and abnormal growth, including cancer.

Her outstanding contribution to science was recognized a relatively long time (three decades) after it was produced, by the Nobel Prize in Physiology or Medicine that she shared in 1986 with Stanley Cohen.

She was born on April 22, 1909 to a wealthy Italian Jewish family in pre-Fascist Turin and died on December 30, 2012, aged 103.

Her life appears as a series of tour-de-force or changes that she was strong and wise enough to overcome brilliantly. The first one was to convince her autocratic father, a mathematician and electrical engineer, that to begin her medical studies at the University of Turin, in 1930, was an appropriate choice for a young woman. He was against this project but she persisted. Her first mentor was Giuseppe Levi, one of Italy’s greatest histologists at that time, who kindled her interest in the nervous system. He taught her the technique, novel at that time, of silver-staining to identify nerve cells under the microscope. Levi was a powerful and effective teacher of science: two of Rita’s fellow students in Levi’s laboratory, Renato Dulbecco and Salvador Luria, also won the Nobel Prize. Under the guidance and protection of Giuseppe Levi, Rita Levi-Montalcini overcame the entrenched sexism pervading medicine at that time.

In 1936 she became a Medical Doctor specialized in Neurology and Psychiatry. It was the year when Mussolini published his manifest by which non-Aryans were banned from all university posts and from practicing medicine.

This was the beginning of a period of hardship and despair, but also perseverance. She assembled a secret laboratory in her bedroom at her parent’s house in Turin and, with rudimentary equipment, worked on the development of the nervous system on chick embryos. Fortunately, her activities remained secret. Their discovery could have resulted in imprisonment or death. She was joined at that time by her former mentor Giuseppe Levi, who emerged from hiding and requested her hospitality.

During that period she read an article written by Viktor Hamburger, an Embryologist at Washington University in Saint-Louis, Missouri, in which he showed that cut off the growing limbs in the chick embryo resulted in the death of the motoneuron of the spinal cord fated to innervate them. He proposed as an explanation to this effect that the target organs produce an “inductive factor”.

They reproduced Hamburger’s results but were not in agreement with his interpretation.

Using the silver-staining technique Levi had taught her, which allowed to follow the fate of the neurons more precisely, Rita realized that neuronal death was the consequence of the absence of a growth-promoting substance, rather than an inductive factor, produced by the target of growing neurons. Publication of this work was refused by an Italian journal because of the non-Aryan names of its authors but was fortunately accepted by the Belgian Archives of Biologie (Levi-Montalcini and Levi, 1942).

Hamburger was intrigued by the different mechanisms of action that had been postulated by them and by him and invited Rita to work in his laboratory for one or two years to reinvestigate this problem with him. In 1947, she left Turin for Saint-Louis, where she was to spend the next 26 years that she considered to happiest and most productive years of her life.

After a year, she was led, by serendipity, as it often happens with great discoveries, to do the critical experiment through which she managed to identify the nerve growth factor that her intuition had suggested to her. A former student of Viktor Hamburger published a short article in 1948 which was to change the direction of her research entirely. In his article, Ed Bueker reported on the results of an experiment he had performed to test the ability of developing nerve fibres to innervate fast-growing tissues. For that purpose he selected a mouse tumour, Sarcoma 180. Grafting the body wall of a chick embryo, that tumour implant became innervated by the adjacent sensory ganglia of the host. As a result, the sensory ganglia providing the fibres to the tumour became larger than the contralateral ones.

Rita and Viktor reinvestigated this effect and noticed that it was different from the one produced by grafting a supernumerary limb: the motoneurons were not more abundant and the tumour graft did not receive extra motor nerves. In contrast, the sympathetic ganglia in the vicinity of the graft became enormously enlarged although their nerve fibres did not join any target but were wandering aimlessly among the cells. The effect was clearly different from that of grafts of normal embryonic tissues. Rita understood that the tumour acted by releasing a growth factor of an unknown nature and not by making available to the nerve fibre a larger-than-visual field of innervation.

She grafted the tumour, not in the embryo itself, but on the chorio-allantoic membrane and got the same results, indicating that the tumour produced a substance which, carried by the blood stream, acted on distant sensory and sympathetic ganglia (1952).

It appeared however that the purification of the factor capable of making the peripheral nerves of sensory and sympathetic ganglia grow, was not feasible on the basis of these in vivo experiments. Hence the search for a simple and more quantitative test. The tissue-culture method, which had started to be developed in certain laboratories at that time, seemed apt to study this problem. A friend of Rita, Herta Meyer, a former colleague in Turin, was at that time in charge of the tissue-culture unit at the Biophysics Institute of the Medical School of Rio de Janeiro directed by Professor Carlos Chagas. Rita obtained a travel grant from the Rockefeller Foundation to join this laboratory and boarded a plane for Brazil in October 1952 with two mice bearing transplants of sarcoma 180 in her handbag. With the help of her host Herta, she set up a culture technique in which a sympathetic ganglion taken from a chick embryo was cultured adjacent to a fragment of the tumour. Twelve hours later nerve fibres had grown out from the entire periphery of the sensory and sympathetic ganglia and spread out radially around to explant like the rays of the sun (I quote her). This was designated as the “NGF halo” and was the most sensible and reliable index of this growth factor in any tissue and in body fluids as well.

This dramatic example of scientific art confirmed the target-derived growth-promoting substance that she has predicted. It remained one of her favourite memories of her scientific success.

This discovery revolutionized neurobiology and endocrinology and set the stage for cell signalling research.

The purification and biochemical characterization of the NGF was achieved thanks to her collaboration with biochemist Stanley Cohen.

Cohen became interested on this phenomenon and had the chance to discover that snake venom and the submandibular gland of male mice were richer sources of NGF than the tumour. It is from snake venom that he succeeded to purify the factor and show that it was a protein. Stanley Cohen then produced an antibody against this molecule which, injected in mice in the five first days of life produced a complete and definitive immunosympathectomy. This technique was utilized in many laboratories to assess the role of the sympathetic nervous system in physiological and pathological conditions. In 1959, Stanley Cohen left Saint-Louis.

At first, NGF was not universally recognized as significant. Rita Levi-Montalcini had to wait until the early 1970s when other similar factors were discovered for the importance of NGF to become undoubtedly evident. The molecular characterization and cloning of the gene was achieved later and it turned out that it was a member of a large family of growth factors acting on the nervous system during development and adult life.

It also appeared that it had more functions that previously thought: not only was it shown to be important in the brain (learning and memory) but its expanded role was demonstrated in other functions in the immune system, fertility and ophthalmology.

After spending more than three decades in Saint-Louis and missing her twin sister Paola, Rita began a gradual return to Rome and became the director of the Institute of Cell Biology at the National Research Council in Rome which, under her guidance, became one of the largest research centres in Italy.

In 1992, she established the Rita Levi-Montalcini Foundation, which supports women from developing countries in establishing a career in science.

Long after she retired she went to the laboratory every day and continued to work and event to publish until she was over 100 years old!

Rita was given one of the most prestigious and rare honours as a lifetime member of the Italian Senate. She took advantage of this position to be an omnipresent advocate for Italian science.

In 2002, she was the founder and president of the European Brain Research Institute (EBRI).

Rita Levi-Montalcini’s life was remarkable in many respects. Because there were so few women in science at the time she started her career, she faced many hurdles in establishing herself as an independent scientist.

She had to endure obstacles due to sexism, religions discrimination, was affected by totalitarianism politics and war, but was able to resist and make her way with majesty.

Primo Levi, the eminent Italian writer who also suffered persecution and bias wrote that Rita was “A tiny lady with an indomitable will and a countenance of a princess”.

Nicole M. Le Douarin