Levi-Montalcini was working with chick embryos in 1938, investigating how
neurons find their way to the limbs they are to innervate, when she was barred
from the University of Turin, a Jew in Mussolini’s Italy. She continued work in
a laboratory she set up in her bedroom in Turin, then in the
the end of this difficult period, there was a seed for what has been one of
most fantastic developments in one field of neuroscience”—the identification of
nerve growth factor (NGF), said Piergiorgio
Strata, president of Italy’s National Institute of Neuroscience,and
a member of the European Dana Alliance for the Brain (EDAB).
The occasion was
symposium for Levi-Montalcini, a founding member of EDAB who died in 2012
at the age of 103. Neuroscientists who knew, worked or studied with
Levi-Montalcini honored her life by elaborating her legacy—a morning's tour
through research that followed the groundbreaking discoveries for which she
Nobel Prize in Physiology or Medicine in
at Washington University in St. Louis after the war, she and Stanley Cohen
(with whom she
shared the Nobel)
identified a compound, expressed by peripheral cells, that attracted spinal
neurons and induced neurite formation, then isolated this substance—NGF—from
tumors, snake venom, and mouse salivary glands—all in the face of relentless
skepticism from the scientific community.
at the symposium, presented by the Italian Cultural Institute and Centro Primo
Levi in NYC, stressed the characteristics that enabled her to flourish
intellectually and prevail in adversity: a powerful, charismatic personality,
enormous drive and passion for her work, and an approach that combined intuition
with analysis. "She often noted that she viewed herself as an artist more than a
scientist," said a Neuron obituary.
importance of this work, speakers said, could hardly be overestimated. "If we
look at the history of 20th century neuroscience, Rita ranks with the giants...
she was the first major molecular neurobiologist," wrote fellow Nobelist (and
member of the Dana Alliance for Brain Initiatives) Eric
Kandel, in a tribute
read at the meeting. "Her extraordinary discovery of NGF affected all aspects of
the first identified growth factor, NGF introduced a radically new concept,
Greene of Columbia University."We knew
from insulin that organs could communicate via substances that went into the
bloodstream. A major implication of Rita's findings was that there was another
means of communication between cells, at short range.” Her inquiry into
embryonic development illuminated key processes in mature neurons—survival,
plasticity, neuroprotection—and beyond, “an explosion of findings within and
outside the nervous system."
Bradshaw of University of California, San
Francisco, called NGF a "Rosetta Stone" that helped decode key aspects of
nervous system function, proteins, receptors, and cancer
reviewed some of his involvement in elaborations of the NGF discovery—beginning
with the sequencing, in collaboration with Ruth Angeletti (who had been
Levi-Montalcini's only PhD student, now at Albert Einstein College of Medicine),
of the NGF molecule. The structure, he said, suggested a compound that acted
like insulin on target cells. "It turned out we were right, but not for all the
idea that NGF was an endocrine-like substance led to pursuit of the receptor,”
Bradshaw said, summarizing research that eventually characterized not one but
two receptors (a fact that “befuddled the field for 15-20 years”) and then to
elucidation of the molecular signaling pathways by which NGF and related
compounds modulate cellular function.
picture started to evolve that these factors were not only involved in growth
and development, but also as regulators in growth disorders, namely cancer…
that these were very important discoveries,” Bradshaw said.
exemplified this importance. "In science, you start working on one thing and end
up with something far different," he said. “NGF led us, in ways we never would
have anticipated, to a potential treatment for brain tumors.”
with studies in the 1990s to explore how NGF regulates genes. Using serial
analysis of gene expression, Greene’s research team identified hundreds of genes
that became more or less active after exposure to the compound. The researchers
then focused on transcription factors—proteins that determine whether genes are
turned on or off. They found that one of these compounds, ATF5, was particularly
abundant in neural progenitor cells, but not in mature neurons or astrocytes,
and that NGF shut down production of ATF5.
led us to the idea that ATF5 is important for proliferation of [stem] cells
that eventually give rise to the brain. When they encounter growth factor, they
turn into differentiated cells and stop proliferating,” Greene said. Neural
progenitor cells that were experimentally deprived of ATF5 differentiated
prematurely and failed to migrate. Cells infected with a retrovirus to keep on
producing the transcription factor never differentiated and continued to
divide—much like a tumor.
wondered: is ATF5 present in glioblastomas?” he said.
It was; cells from
29 of these highly virulent, virtually incurable tumors all expressed the
transcription factor. When the researchers silenced ATF5 in cultured
glioblastoma cells, the cells died.
vivo studies, the
researchers gave mice with experimentally induced glioblastomas subcutaneous
injections of a molecule that hybridized dominant-negative ATF5 protein, which
neutralizes ATF5, with penetratin, a peptide that crosses the blood-brain
days of treatment, tumor cells began to die; 19 days and 6 months later, the
tumors had disappeared on MRI. Treated animals all survived for 6 months, while
60% of the others died. There was no apparent kidney, brain, liver, or blood
work proceeds with other animals, “we’re collecting data to go to the FDA for
possible clinical trials,” Greene said. The approach “could work for other
tumors as well.”
of the European Brain Research Institute in Rome (which Levi-Montalcini helped
establish in 2002), described research linking the NGF system to Alzheimer’s
disease pathology, and suggesting a novel treatment strategy.
antibodies that target NGF, he showed that neutralizing the growth factor in
the brains of adult mice initiated a process of neuroinflammation and
neurodegeneration. While the effect on cholinergic neurons—a key population in
Alzheimer’s disease (AD)—was first implicated, it became clear that astrocytes
and glia were compromised as well.
studies characterized this neurodegeneration process as an imbalance between
NGF and a precursor protein, proNGF, and showed that the same result could be
achieved by modifying mouse brain cells to overexpress proNGF.
has been exploring ways to “strengthen the balance by increasing NGF.” When
mice, genetically modified to express AD-like pathology, were given a modified
form of NGF intranasally, amyloid plaques regressed, and learning and memory
may be a viable candidate for a non-invasive therapeutic approach to AD,” he
said. “We’re collaborating with the pharmaceutical industry to get clinical
toward the future of NGF-related research, Cattaneo cited an "agenda" that
Levi-Montalcini proposed in 2009, at the age of 100. In addition to work (like
the studies described above) aiming to develop its therapeutic potential, she
urged investigations of the NGF system’s role earlier in embryonic development
than the nervous system, and in more primitive species.
Her agenda called
for studies of NGF in other tissues, particularly the reproductive system. “Rita
predicted it would be found to participate in processes like activation of sperm
or implantation of ova,” Cattaneo said.
scientific intuitions were still reliable, he said. In a paper published
three years later,
researchers described their work identifying a substance in the semen of diverse
mammals that induces ovulation. It was NGF.