Unwavering dedication to discovering what makes cells grow.
All living things, including humans, start as single cells. With time, that single cell grows bigger, divides into more cells, and differentiates into various types of cells to make up the complex human you are today. However, the cells in our body don’t stop growing and dividing as we become older. In fact, each day, our body replaces 330 billion cells!
This means that in about 80 days from now, all of the cells that are in your body will be replaced by entirely new cells. But, how do your cells know when they should grow, divide, and differentiate? Dr. Rita Levi-Montalcini, an Italian neuroscientist, discovered the first growth factor, a signaling molecule that tells cells that they should grow! In 1986, she won the Nobel Prize in Physiology or Medicine for this enormous discovery.
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A Nerve-Wracking Road
Dr. Rita Levi-Montalcini was born in Turin, Italy in 1909 to Italian-Jewish parents. She grew up in a time where women were expected to limit their expertise to the home, but Rita desired more. When her governess died of stomach cancer, she decided that she must study medicine.
After receiving her father’s reluctant consent, she enrolled at the University of Turin at the age of 21 and graduated with an M.D., summa cum laude in 1936. She proceeded to specialize in neurology and psychiatry in 1940. Drawn to a famous teacher, Dr. Giuseppe Levi, she became an intern at the Institute of Anatomy. It was here that she realized her love for research. Here, she began studying the development of the nervous system using chick embryos.
But, her research at the university didn’t last long. This was a politically tumultuous time in Italy; Benito Mussolini, a horrific dictator and Adolf Hitler’s ally, had just come to power. Inspired by the Germans, he passed anti-semitic laws prohibiting Jews from practicing medicine and working in universities. Rita promptly withdrew but she was not deterred. She built a laboratory in her bedroom, determined to continue studying neurons (Read our post on Elaine Hsiao to learn more about neurons). She fashioned scalpels out of sewing needles, convinced farmers she needed eggs for her (nonexistent) children, and used these as tools to study how embryonic nerve tissue in chick embryos develops into specialized tissue types.
Conflicting Conjecture Creates Collaboration
Before Levi-Montalcini began examining the origin of specialized tissues, Viktor Hamburger of Washington University had a theory about nerve differentiation that was widely accepted. He had conducted an experiment where he removed the developing limbs in chick embryos to see what would happen to the nerve cells that were supposed to grow, differentiate, and reach that limb.
He saw that when the limb was removed, the nerve cells that begin their journey of growth near the spinal column were much smaller and didn’t reach the region where the limb used to be. He theorized that the specialization of nerve cells depends on the destination they are headed to. He reasoned that some factor was present in the limb that told nerve cells to differentiate. In the absence of the limb, there was no specialization factor, so the nerve cells could no longer differentiate and grow towards where the limb used to be.
Dr. Rita Levi-Montalcini repeated this experiment and saw a similar result. However, her theory differed from Hamburger’s. She proposed that the nerve cells did differentiate, but the cells soon died without sustenance that was provided in the limb. When the nourishing factor was absent, the nerve no longer grew. Contrary to Hamburger’s differentiation factor theory, Levi-Montalcini believed that a growth factor is what allowed the nerves to grow.
When Hamburger read Levi-Montalcini’s contrasting work, he invited her to Washington University to work with him on solving this problem. They decided to study cancer cells because cancer is a form of abnormal cell growth. They took mouse cancer cells and grafted them into a 3-day old chick embryo.
To their astonishment, a few days after putting the cancer cells into the embryo, nerve fibers had grown from the chick spinal column into the cancerous tissue. Something the cancer cells were doing allowed nerve fibers to grow! To see whether this curious phenomenon requires direct contact with the cancerous tissue, they repeated this cancer-in-a-chick-embryo experiment, except this time they made sure to prevent any direct contact between the embryonic tissue and the cancerous tissue. They were only connected via the circulatory system. They saw the same result: nerve cells grew towards the cancer! Rita Levi-Montalcini reasoned that the growth factor must be soluble and carried by the bloodstream, telling nerve cells when and where to grow.
Now, it was time to isolate this mysterious factor. With the assistance of Stanley Cohen, Levi-Montalcini isolated a fraction of the cancer cells that contained proteins and nucleic acids (macromolecules that make up DNA and RNA; to learn more about DNA, read our post on Flossie Wong-Staal). To figure out whether it was nucleic acids or proteins, Cohen used an innovative technique to eliminate the nucleic acids. He added snake venom to the cells, because the venom degrades nucleic acids. They thought that if the nucleic acids were the growth factor, then these cells would no longer be able to promote nerve growth.
To their utter disbelief, adding snake venom led to an increase in nerve growth! It became clear that the snake venom itself contained the growth factor that Rita Levi-Montalcini had been chasing! This happy accident allowed them to directly isolate the factor of interest from snake venom without having to deal with cancer cells at all. After a series of laborious purification steps, they were able to isolate a protein that they called nerve growth factor (NGF). This protein alone was sufficient to cause nerve fibers to grow! Thus was found the first growth factor! Dr. Rita Levi-Montalcini and Dr. Stanley Cohen share the Nobel Prize for this fascinating discovery.
In the face of adversity, be like Levi-Montalcini
NGF was the first of many growth factors to be discovered. The discovery of NGF changed the way scientists thought about and studied nerve growth and differentiation. Not to mention, NGF could be used as a way to battle disorders such as Alzheimer’s, dementia, and even cancer!
After having faced tremendous prejudice and countless hardships, Rita Levi-Montalcini spent the latter part of her career working to ensure that scientists had the opportunities and resources they needed to succeed. She was the president of the Italian Multiple Sclerosis Association, a member of the Pontifical Academy of Sciences, and served on the Italian Senate as a Senator for life.
Her 100th birthday was celebrated with much flair at Rome’s city hall. Despite many adversities, Dr. Levi-Montalcini didn’t shy away from them. In fact, she said “if I had not been discriminated against or had not suffered persecution, I would never have received the Nobel Prize.” She embraced the external forces that shaped her into who she was: a determined, fearless scientist and an inspiration to us all.
Written by Manasvi Verma
Edited by Katie Fraser and Madelyn Leembruggen
Illustrations and Portrait by Ashley Hayden
Sources and additional readings:
Finding the Good in the Bad: A Profile of Rita Levi-Montalcini, Scientific American
Women who changed Science, The Nobel Prize
Rita Levi-Montalcini, Jewish Women’s Archive
Nerve Growth Factor, The Embryo Project
Rita Levi-Montalcini and the discovery of NGF, the first nerve cell growth factor, Archives Italiennes de Biologie