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Neurotrophic Factors


Scientists have recently discovered a family of proteins called neurotrophic factors. These substances are responsible for the growth and survival of neurons during development, and for maintaining adult neurons. Neurotrophic factors also are capable of making damaged neurons regrow their processes in a test tube and in animal models. Because of this, they represent exciting possibilities for reversing devastating brain disorders, including Alzheimer's disease, Parkinson's disease and Lou Gehrig's disease.
For decades, scientists believed that brain cells of the central nervous system could not regrow following damage due to trauma such as head injury or disorders such as Alzheimer's disease. Treatments did not exist. The outlook was bleak.
But now that thinking has been turned upside down. Scientists recently have discovered a whole family of proteins called neurotrophic factors -- derived from the Greek "neuro" for nerve and "troph" for nourish. These proteins play a crucial role in the development and survival of nerve cells, or neurons, and in supporting adult neurons to keep them healthy throughout life.

Recent research shows that neurotrophic factors are:

Present in early development of the nervous system and are responsible for the initial growth and development of neurons in the peripheral and central nervous systems.
Released by target tissue of a growing neuron and can determine whether a neuron reaches its target during development; neurons which do not reach the target die.
Capable of making damaged neurons regrow their processes in a test tube and in animal models and, thus, represent exciting possibilities for reversing devastating disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.
Scientists are now looking for ways to harness neurotrophic factors to induce the regrowth of damaged neurons and improve symptoms of patients with neurological diseases. Neurotrophic factors exert their effects on neurons through several receptors -- proteins on the surface of cells into which neurotrophic factors fit much the way a key fits a lock.

Neurotrophic factors, produced by several body tissues including muscle, act by attaching to receptors on the tips, or nerve terminals, and on the cell body -- which contains the nucleus -- of neurons. The signal can then be carried through the axon, the neuron's elongated fiberlike extension, which can be as long as a yard, to the cell body where it tells the cell what to do.

Thus far, scientists have identified several neurotrophic factor receptors -- which also may be potential targets for therapy. A receptor called trk is required for the action of nerve growth factor (NGF), the first neurotrophic factor, which was discovered 40 years ago. NGF affects primarily neurons using the neurotransmitter acetylcholine in the basal forebrain, sensory neurons and sympathetic neurons that regulate organs such as the heart and lungs. Relatives of trk are receptors for other neurotrophic factors -- trkB seems to be a receptor for brain-derived neurotrophic factor; and trkC for neurotrophin-3.
Scientists continue to match up various neurotrophic factors and their possible roles in maintaining neurons and in neurological disorders. Meanwhile, ciliary neurotrophic factor, insulin-like growth factor-1 and brain-derived neurotrophic factor are in human clinical trials for treating ALS.
These patients may be among the first to benefit from a therapeutic neurotrophic factor because treatment for ALS does not need to cross the blood-brain barrier. Since ALS involves the loss of motor neurons whose axons are located in the peripheral nervous system, drugs can be delivered by injection. Success with these investigations should encourage scientists to devise treatments for disorders of the central nervous system such as Parkinson's disease and Alzheimer's disease.
While therapeutic agents made from neurotrophic factors are probably three to ten years away, research holds tremendous promise. Moreover, dozens of neurotrophic factors may yet be discovered and these may be important for treating other neurodegenerative disorders and trauma.
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In the brain, a neurotrophic factor is released by a neuron or a support cell, such as an astrocyte, and binds to a receptor on a nearby neuron. This binding results in the production of a signal which is transported to the nucleus of the receiving neuron where it results in the increased production of proteins associated with neuronal survival and function.
Illustration by Lydia Kibiuk, Copyright © 1994 Lydia Kibiuk.


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www.nobelprize.org

The Nobel Prize in Physiology or Medicine 1986
Presentation Speech
Presentation Speech by Professor Kerstin Hall of the Karolinska InstituteTranslation from the Swedish text
Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

We have all been small infants who have grown tall. It is growth hormone, released from the pituitary gland, which regulates growth after birth. Lack of this hormone during infancy results in growth retardation, and a growth hormone deficient man is a minicopy of his potential self. The pituitary growth hormone, however, has no direct growth promoting effect on cells, and growth before birth occurs independently of growth hormone.
We are all derived from one single cell which carries the genetic material coding for all the different characteristics expressed in the thousands of billions of cells present in adult man. This first cell divides into two identical daughter cells. These daughter cells grow and then they too divide. During the cell divisions which follow, the cells begin to express specific characteristics, in other words, they differentiate. The newborn infant already has all the different types of cells found in the adult.
The pattern of growth and differentiation has long been established, but the mechanisms regulating prenatal development remained unknown - growth hormone does not control these events. The discovery of growth factors in tissues other than the pituitary led to a new understanding - growth and differentiation are regulated by signal substances released from cells and acting on neighbouring cells. The first such signal substances to be identified were nerve growth factor (NGF) and epidermal growth factor (EGF). The discovery of NGF by Rita Levi-Montalcini and EGF by Stanley Cohen initiated a new era in the research area of growth and differentiation and was followed by the identification of several other growth factors released by different types of cells.
It all began when the Italian developmental biologist Rita Levi-Montalcini was invited to Viktor Hamburgers laboratory in St. Louis, Missouri. There she repeated a previously performed study, but the conclusion she reached was different. When transplanting mouse tumour to chick embryos she found an outgrowth of certain nerve fibres in the chicken. The nerve outgrowth was similar when the transplantation was performed without direct contact between the tumour and the chick embryo. Rita Levi-Montalcini concluded that the tumour released a substance which promoted nerve growth. She developed a bioassay using cultured nerve cells for identification of the factor.
The biochemist Stanley Cohen joined the research group in the early 1950s. He observed that saliva and salivary gland from the male mouse contained far more NGF than the mouse tumours. He purified NGF from salivary glands and raised antibodies against NGF.
The discovery, identification and isolation of NGF created a breakthrough in the research field of developmental neurobiology: For the first time a chemically well-characterized substance became available for use in studies of nerve growth. Rita Levi-Montalcini showed, in a series of brilliantly performed studies, that NGF is not only necessary for the survival of certain nerves but also regulates the directional growth of the nerve fibres. The nerve cells die when NGF is blocked by antibodies. NGF is produced by the target cells which lure the nerve fibres to grow in the direction. Injections of NGF into the brain cause the outgrowth of specific nerve fibres. This neurotropic effect of NGF offers an explanation of how nerve fibres can find their way through the tangle of nerves in the brain.
Stanley Cohen, who purified NGF, is also the discoverer of epidermal growth factor or EGF. While investigating the effects of NGF he observed that injection of salivary gland extracts to newborn mice accelerated their development. They displayed precocious opening of their eyelids and early eruption of their teeth. Stanley Cohen realized that the salivary gland extracts contained some additional growth factor apart from NGF. He isolated, characterized and established the amino acid sequence of this factor and showed that it accelerated the healing of corneal wounds.
EGF has proven to be a general growth factor with action not only on epithelial cells but also on a large variety of other cells. A prerequisite for its action is the presence of specific binding sites, termed receptors, on the surface of the target cells. Stanley Cohen isolated and characterized the EGF-receptor. He discovered that the receptor consisted of one part on the outside of the cell membrane, which captures EGF, and the other part on the inside of the cell which displays enzyme activity. When EGF binds to the receptor on the outside of the cell it activates this internal enzyme activity. Gradually a new concept has emerged - this type of enzyme activity is a general pathway by which the action of growth factors is initiated. Furthermore, some viral oncogenes cause tumour growth code for proteins with the same kind of enzyme activity as the EGF receptor.
NGF and EGF were discovered in mice, but since then one has moved from mouse to man. The chemical structures of human NGF and EGF are established today, and recombinant human NGF and EGF are produced by DNA-technology. This has opened the way for the use of NGF and EGF in clinical medicine. Deficiency or overproduction of these growth factors may be of importance in the pathogenesis of malformations and errors of development, degenerative changes with regeneration defects, delayed wound healing and tumour diseases. The role of NGF in diseases of the central nervous system, such as senile dementia, and the possibility of using NGF after damage to peripheral nerves are currently being explored. Application of EGF has already been shown to enhance the healing of wounds of cornea, skin and intestine. Autotransplantation of skin rapidly cultivated outside the body with the help of EGF can be used to cover burns.
Rita Levi-Montalcini and Stanley Cohen were the first to discover and isolate growth factors. Their pioneering contributions stimulated the search for other growth factors and several such substances have been characterized today. Their work has opened up a research field of potential importance to future medicine. Rita Levi-Montalcini and Stanley Cohen have advanced our knowledge from a stage when growth and differentiation could only be described as phenomena and growth factors were unknown, to a situation today when the role of growth factors in cell proliferation, organ differentiation, and tumour transformation is generally recognized. Rita Levi-Montalcini is the great developmental biologist who showed how the outgrowth of the nerves was regulated. Stanley Cohen is the brilliant biochemist who purified the first growth factors and improved our understanding about how a growth signal from the outside is relayed into the cells.
As a representative of the Nobel Assembly at the Karolinska Institute, I convey to you the sincere congratulations of the Assembly and ask you now to receive your Prize from the hands of His Majesty the King.
From Nobel Lectures, Physiology or Medicine 1981-1990, Editor-in-Charge Tore Frängsmyr, Editor Jan Lindsten, World Scientific Publishing Co., Singapore, 1993
Copyright © The Nobel Foundation 1986

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Rita Levi-Montalcini
The Nobel Prize in Physiology or Medicine 1986
Autobiography
My twin sister Paola and I were born in Turin on April 22, 1909, the youngest of four children. Our parents were Adamo Levi, an electrical engineer and gifted mathematician, and Adele Montalcini, a talented painter and an exquisite human being. Our older brother Gino, who died twelve years ago of a heart attack, was one of the most well known Italian architects and a professor at the University of Turin. Our sister Anna, five years older than Paola and myself, lives in Turin with her children and grandchildren. Ever since adolescence, she has been an enthusiastic admirer of the great Swedish writer, the Nobel Laureate Selma Lagerlöf, and she infected me so much with her enthusiasm that I decided to become a writer and describe Italian saga "à la Lagerlöf". But things were to take a different turn.

The four of us enjoyed a most wonderful family atmosphere, filled with love and reciprocal devotion. Both parents were highly cultured and instilled in us their high appreciation of intellectual pursuit. It was, however, a typical Victorian style of life, all decisions being taken by the head of the family, the husband and father. He loved us dearly and had a great respect for women, but he believed that a professional career would interfere with the duties of a wife and mother. He therefore decided that the three of us - Anna, Paola and I - would not engage in studies which open the way to a professional career and that we would not enroll in the University.

Ever since childhood, Paola had shown an extraordinary artistic talent and father's decision did not prevent her full-time dedication to painting. She became one of the most outstanding women painters in Italy and is at present still in full activity. I had a more difficult time. At twenty, I realized that I could not possibly adjust to a feminine role as conceived by my father, and asked him permission to engage in a professional career. In eight months I filled my gaps in Latin, Greek and mathematics, graduated from high school, and entered medical school in Turin. Two of my university colleagues and close friends, Salvador Luria and Renato Dulbecco, were to receive the Nobel Prize in Physiology or Medicine, respectively, seventeen and eleven years before I would receive the same most prestigious award. All three of us were students of the famous Italian histologist, Giuseppe Levi. We are indebted to him for a superb training in biological science, and for having learned to approach scientific problems in a most rigorous way at a time when such an approach was still unusual.

In 1936 I graduated from medical school with a summa cum laude degree in Medicine and Surgery, and enrolled in the three year specialization in neurology and psychiatry, still uncertain whether I should devote myself fully to the medical profession or pursue at the same time basic research in neurology. My perplexity was not to last too long.

In 1936 Mussolini issued the "Manifesto per la Difesa della Razza", Mussolini's 1938 Manifesto della Razza and the subsequent introduction of laws barring Jews from academic and professional careers signed by ten Italian 'scientists'.

The manifesto was soon followed by the promulgation of laws barring academic and professional careers to non-Aryan Italian citizens. After a short period spent in Brussels as a guest of a neurological institute, I returned to Turin on the verge of the invasion of Belgium by the German army, Spring 1940, to join my family. The two alternatives left then to us were either to emigrate to the United States, or to pursue some activity that needed neither support nor connection with the outside Aryan world where we lived. My family chose this second alternative. I then decided to build a small research unit at home and installed it in my bedroom. My inspiration was a 1934 article by Viktor Hamburger reporting on the effects of limb extirpation in chick embryos. My project had barely started when Giuseppe Levi, who had escaped from Belgium invaded by Nazis, returned to Turin and joined me, thus becoming, to my great pride, my first and only assistant.

The heavy bombing of Turin by Anglo-American air forces in 1941 made it imperative to abandon Turin and move to a country cottage where I rebuilt my mini-laboratory and resumed my experiments. In the Fall of 1943, the invasion of Italy by the German army forced us to abandon our now dangerous refuge in Piemonte and flee to Florence, where we lived underground until the end of the war.

In Florence I was in daily contact with many close, dear friends and courageous partisans of the "Partito di Azione". In August of 1944, the advancing Anglo-American armies forced the German invaders to leave Florence. At the Anglo-American Headquarters, I was hired as a medical doctor and assigned to a camp of war refugees who were brought to Florence by the hundreds from the North where the war was still raging. Epidemics of infectious diseases and of abdominal typhus spread death among the refugees, where I was in charge as nurse and medical doctor, sharing with them their suffering and the daily danger of death.

The war in Italy ended in May 1945. I returned with my family to Turin where I resumed my academic positions at the University. In the Fall of 1947, an invitation from Professor Viktor Hamburger to join him and repeat the experiments which we had performed many years earlier in the chick embryo, was to change the course of my life.

Although I had planned to remain in St. Louis for only ten to twelve months, the excellent results of our research made it imperative for me to postpone my return to Italy. In 1956 I was offered the position of Associate Professor and in 1958 that of Full Professor, a position which I held until retirement in 1977. In 1962 I established a research unit in Rome, dividing my time between this city and St. Louis. From 1969 to 1978 I also held the position of Director of the Institute of Cell Biology of the Italian National Council of Research, in Rome. Upon retirement in 1979, I became Guest Professor of this same institute.

From Les Prix Nobel. The Nobel Prizes 1986, Editor Wilhelm Odelberg, [Nobel Foundation], Stockholm, 1987

This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate. To cite this document, always state the source as shown above.



For more updated biographical information, see:
Levi-Montalcini, Rita, In Praise of Imperfection: My Life and Work. Basic Books, New York, 1988.



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