Pre-Print - Rita Levi-Montalcini
- By: FUNblog
- On: 06/25/2020 12:23:17
- In: Project Divine Pre-Prints - Diversity in Neuroscience
Contributor: Judith M. Ogilvie
Topics: neural development; nerve growth factor; neural signaling
References: Levi-Montalcini and Booker, 1960a; Levi-Montalcini and Booker, 1960b
Description: These two papers are central to the Nobel Prize winning work of Rita Levi-Montalcini. Levi-Montalcini with Stanley Cohen received the 1986 Nobel Prize in Physiology or Medicine “for their discoveries of growth factors (“The Nobel Prize in Physiology or Medicine 1986,” n.d.).” In these papers, the authors describe the discovery that mouse sarcoma tumors release a substance that induces growth and differentiation of sympathetic neurons, which was subsequently isolated and named nerve growth factor. The introductory paragraphs of the first of these two papers provide a summary of the experiments that preceded this work and clearly lays out three unanswered questions that follow. Levi-Montalcini and Booker begin by demonstrating that the growth promoting effects previously reported in vitro in chick, mice, and rats is also produced in sensory and sympathetic ganglia from human fetuses (R. Levi-Montalcini & Booker, 1960d). The primary focus of the first paper is on the in vivo extension of this work, demonstrating that injections of the purified substance in newborn and adult mice have dramatic growth promoting effects on the sympathetic ganglia, resulting in an increase in both the number and size of the neurons. In the second paper, Levi-Montalcini and Booker demonstrate that inhibition of the nerve growth factor leads to destruction of the sympathetic ganglia in several mammalian species (R. Levi-Montalcini & Booker, 1960b). Together the articles provide gain-of-function and loss-of-function evidence that nerve growth factor is both necessary and sufficient for development and maintenance of the sympathetic ganglia.
A third paper by Stanley Cohen, with whom Levi-Montalcini shared the Nobel Prize, is included in the same volume (Cohen, 1960). His work, summarized in these two papers, describes the biochemical isolation of the substance and the production of the antibody.
Value: In a manner typical of classic papers but less common today, the inquiry-based nature of science is emphasized rather than hypothesis-driven experiments. A study that began with experiments on mouse tumors led to a fundamental and far-reaching discovery on the mechanisms underlying the development of the nervous system. Serendipity played a key role as illustrated in the authors' description of their plan to use snake venom as a source of proteolytic enzymes only to find that the venom contained the very same growth-inducing effect they were investigating. The leap from snake venom to the mouse salivary gland was the result of keen insights.
Instructors may wish to include the third paper by Cohen (1960). This paper is not necessary for understanding the work by Levi-Montalcini. Classic biochemical protein isolation techniques are described in detail, although these techniques have largely been replaced in modern biochemistry labs. This may be enlightening for students with a biochemistry background, but may be more challenging for others.
Biographical information: Rita Levi-Montalcini had a remarkable life story (Rita Levi-Montalcini, 1988). She and her twin sister were born on 22 April 1909 in Turin Italy, the youngest of four children raised in an intellectual Jewish family. Although her father expected his daughters to follow a traditional role of marriage and family, she persuaded him to allow her to pursue a professional career in medicine with her cousin, Eugenia Sacerdote de Lustig (Cowan). Since math and science were considered unnecessary for a girl's education, a private tutor was hired to prepare them for medical school. They were among four women students in a class of 500 men at University of Turin Medical School (Deutsch, p.85).
After completing her medical degree and unsure whether to pursue a career in research or medicine, Levi-Montalcini chose to continue her training, specializing in neurology and neuroanatomy under Giuseppe Levi, the foremost Italian histologist of the time (Nobel Prize Bio). Half a world away, Victor Hamburger's reputation as a leading developmental biologist was solidified by his work establishing the chick embryo in ovo as a model organism and subsequent discoveries (Ribatti). He used this system to analyze the relationship between the wing bud and spinal neurons during development. Aware of Levi's reputation, he sent a reprint of his studies to Levi who shared it with Levi-Montalcini. This paper was to have a profound and lasting effect on her future career (Cowan).
In 1938 Levi-Montalcini's academic work came to a halt when Mussolini issued the “Manifesto for the Defense of the Race.” (Nobel bio) Jews could no longer be employed at state institutions, including schools and universities, nor could they practice medicine. For a brief period in 1939, she continued her training in Brussels, but as the threat to Jews spread across the continent, she returned home to Turin. Determined to continue her research and now intrigued by Hamburger's results, she set up a small lab in her bedroom using fertilized eggs purchased from a local farmer. She worked there with Levi until 1941 when Allied bombardment of Turin forced her family to retreat to their country cottage. There she again set up a small lab, continuing her research until the German invasion of Italy in 1943. Her family went into hiding in Florence until Italy was liberated in 1944 (Nobel Bio).
After the war, she resumed her position at the University of Turin and published the work that she had done in her makeshift laboratory during the war. This work built on ideas that stemmed from Hamburger's 1934 paper and caught his attention. Now chair of the Department of Zoology at Washington University, Hamburger invited Levi-Montalcini to visit his lab in 1947 (Cowan). What was intended to be a 1 year stay, became a long and fruitful collaboration that extended many decades. Recognizing the need for expertise in biochemistry to understand the mechanism underlying their anatomical observations, Hamburger recruited Stanley Cohen to the Zoology Department (Cowan). Here, their groundbreaking work on nerve growth factor took place. Levi-Montalcini was promoted to associate professor of Zoology in 1951 and full professor in 1958. In 1969 she established a second laboratory in Rome, dividing her time between Italy and St. Louis. She retired from Washington University in 1977 to become the director of the Institute of Cell Biology of the Italian National Council of Research, where she continued to work as a guest professor well after her retirement in 1979 (Missouri Women Bio).
In 1986, Levi-Montalcini was awarded the Nobel Prize in Physiology or Medicine with Stanley Cohen for “for their discoveries of growth factors (Nobel website).” The omission of Victor Hamburger from the Nobel Prize award led to a rift between these collaborators that sometimes overshadowed the important contributions of each of these scientists (Cowan, Ribatti)(Cowan, 2001)(Ribatti, 2016). Coming from a background where she was expected to limit her aspirations to that of a wife and mother, Levi-Montalcini chose to do neither and instead overcame many obstacles to become one of the most important neuroscientists of her generation.
Rita Levi-Montalcini died on December 30, 2012 at the age of 103, becoming the longest-lived Nobel Laureate.
Audience: These papers would be appropriate for mid-level to advanced undergraduate courses including introductory neuroscience or developmental biology courses or more specialized courses in developmental neuroscience, neurochemistry, neuropharmacology, or related subjects.
Cohen, S. (1960). Purification of a Nerve-Growth Promoting Protein from the Mouse Salivary Gland and Its Neuro-Cytotoxic Antiserum. Proceedings of the National Academy of Sciences, 46(3), 302–311. https://doi.org/10.1073/pnas.46.3.302
Cowan, W. M. (2001). Viktor Hamburger and Rita Levi-Montalcini: The path to the discovery of nerve growth factor. Annual Review of Neuroscience, 24, 551–600. https://doi.org/10.1146/annurev.neuro.24.1.551
Levi-Montalcini, R., & Booker, B. (1960a). Destruction of the sympathetic ganglia in mammals by an antiserum to a nerve-growth protein. Proceedings of the National Academy of Sciences, 46(3), 384–391. https://doi.org/10.1073/pnas.46.3.384
Levi-Montalcini, R., & Booker, B. (1960b). Destruction of the sympathetic ganglia in mammals by an antiserum to a nerve-growth protein. Proceedings of the National Academy of Sciences of the United States of America, 46(3), 384–391. https://doi.org/10.1073/pnas.46.3.384
Levi-Montalcini, R., & Booker, B. (1960c). Excessive Growth of the Sympathetic Ganglia Evoked by a Protein Isolated from Mouse Salivary Glands. Proceedings of the National Academy of Sciences, 46(3), 373–384. https://doi.org/10.1073/pnas.46.3.373
Levi-Montalcini, R., & Booker, B. (1960d). Excessive growth of the sympathetic ganglia evoked by a protein isolated from mouse salivary glands. Proceedings of the National Academy of Sciences of the United States of America, 46(3), 373–384. https://doi.org/10.1073/pnas.46.3.373
Ribatti, D. (2016). The failed attribution of the Nobel Prize for Medicine or Physiology to Viktor Hamburger for the discovery of Nerve Growth Factor. Brain Research Bulletin, 124, 306–309. https://doi.org/10.1016/j.brainresbull.2016.02.019The Nobel Prize in Physiology or Medicine 1986. (n.d.). Retrieved June 4, 2019, from NobelPrize.org website: https://www.nobelprize.org/prizes/medicine/1986/levi-montalcini/facts/