Gerald Fischbach | |
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Born | Gerald D. Fischbach November 15, 1938 |
Alma mater | Colgate University, Weill Cornell Medical College of Cornell University |
Occupation | Neuroscientist |
Gerald D. Fischbach (born November 15, 1938) is an American neuroscientist. He received his M.D. from the Weill Cornell Medical College of Cornell University in 1965 before beginning his research career at the National Institutes of Health in 1966, where his research focused on the mechanisms of neuromuscular junctions. After his tenure at the National Institutes of Health, Fischbach was a professor at Harvard University Medical School from 1972 to 1981 and from 1990 to 1998 and the Washington University School of Medicine from 1981 to 1990. In 1998, he was named the director of the National Institute of Neurological Disorders and Stroke before becoming the Vice President and Dean of the Health and Biomedical Sciences, the Dean of the Faculty of Medicine, and the Dean of the Faculty of Health Sciences at Columbia University from 2001 to 2006. [1] Gerald Fischbach currently serves as the scientific director overseeing the Simons Foundation Autism Research Initiative. [2] Throughout Fischbach's career, much of his research has focused on the formation and function of the neuromuscular junction, which stemmed from his innovative use of cell culture to study synaptic mechanisms. [3]
Fischbach attended Colgate University in Hamilton, NY, where he was a four-year recipient of the New York State Regents Scholarship. He graduated magna cum laude with high honors in mathematics receiving a Bachelor of Arts degree in Mathematics and Chemistry. Fischbach was also elected a member of Colgate University's Phi Beta Kappa chapter in 1960. After graduating from Colgate University, Fischbach attended Weill Cornell Medical College of Cornell University, where he was a recipient of the New York State Medical Scholarship from 1962 to 1965 and the Polk Award for Undergraduate Research in 1965, before graduating with his M.D. that same year. Additionally, Fischbach received an honorary master's degree from Harvard University in 1978 and an honorary Doctor of Science degree from Colgate University in 2003. After graduating medical school, Fischbach interned at the University of Washington hospital in Seattle, Washington before beginning his research career at the National Institutes of Health in 1966. [1] Fischbach is married to Ruth L. Fischbach, who currently serves as a Professor of Bioethics in Psychiatry at Columbia Presbyterian Medical Center. They have four children. [4]
Fischbach began his research career at the National Institutes of Health, where he served as a senior surgeon at the National Institute of Neurological Disorders and Stroke (NINDS) before becoming a fellow at the National Institute of Child Health from 1966 to 1973. [1] [5] Much of Fischbach's research concentrated on the mechanisms controlling action potentials and synapses, from which he pioneered the use of neuron and muscle cell culture to study neuromuscular junctions. [3] Fischbach used this technique to reconstruct neuromuscular junctions from dissociated spinal cord and muscle cells from chick embryos to show that functional synaptic connections reformed and were capable of sending spontaneous or induced action potentials. However, cultures containing isolated spinal cord cells were unable to send similar action potentials. [6] This technique proved to be an important model for further studies to determine the essential mechanisms controlling neuromuscular junction development and maintenance. [1] [5] Towards the end of his tenure at the National Institutes of Health, Fischbach began to search for motor neuron molecules responsible for regulating the number of acetylcholine receptors on postsynaptic cells. This research project culminated in 1993 with the isolation of the ARIA (acetylcholine receptor inducing activity) protein, which is a member of the neuregulin family and is responsible for stimulating the production of acetylcholine receptors in postsynaptic muscle tissue. [1] [7]
After his time at the National Institutes of Health, Fischbach obtained a position as an associate professor at Harvard Medical School's Department of Pharmacology in 1973. By 1978 he obtained tenure and became a full professor, and continued teaching at Harvard University for the next three years. After a nine-year stint at Washington University School of Medicine in St. Louis, Missouri, he returned to Harvard to serve as the Nathan Marsh Pusey Professor of Neurobiology and Chairman of the Neurobiology Departments of both Harvard Medical School and Massachusetts General Hospital from 1990 to 1998. [1] During his years as an associate professor, he researched the development of precursor muscle cells, specifically the development of acetylcholine receptors on embryonic chick pectoral muscles. [8] Later on he continued his research on ARIA that he started at the National Institutes of Health, specifically focusing on the expression of the protein's isoforms and their effects on tyrosine kinases. In 1993, Fischbach was involved with the founding of the Mind, Brain, Behavior Institute. This inter-disciplinary program aims to research the different structures, evolution, and development of the nervous system in order to better understand human behavior. [9]
Gerald Fischbach spent nine years at the Washington University School of Medicine, where he served as the Edison Professor of Neurobiology and Head of the Department of Anatomy and Neurobiology. [1] During his time here, Fischbach continued his work on the ARIA protein. When ARIA isolated from chick embryo brain was applied to chicken myotubes, which are developing chicken muscle fibers, it was shown to increase the rate of insertion of acetylcholine receptors into chicken myotube membranes. This indicated ARIA could play a role in acetylcholine receptor insertion in neuromuscular junctions. Additionally, it was demonstrated that ARIA stimulated the transcription of α acetylcholine receptor subunits leading to an increase in α subunit messenger RNA (mRNA) and precursors, but had no effect on the mRNA levels of the γ or δ acetylcholine receptor subunits. This indicated that the amount α acetylcholine receptor subunit limits the synthesis and subsequent insertion of acetylcholine receptors into chicken myotube membranes. [10]
In addition to his ARIA work, Fischbach also researched rapid desensitization of glutamate receptors in chicken spinal cord and rat hippocampal neurons. Using focal ionophoresis and pressure injections to apply glutamate and other agonists including NMDA, AMPA, and kainate to different regions of the neurons, he noticed that certain hot spots were desensitized more rapidly that other sites on the neuron. Fischbach and his collaborators hypothesized that these hot spots may be located at synapses between neurons, where clusters of glutamate receptors were present. [11]
Fischbach returned to the NIH in 1998 when he was named director of the National Institute of Neurological Disorders and Stroke (NINDS), a division of the NIH that supports research on the brain and nervous system. While he was director, Fischbach oversaw a staff of more than 700 and an annual budget of about $800 million. [5] This money was used to support research by private and public organizations across the country as well as scientists working in labs at NINDS. [5] Fischbach accomplished many things while director of NINDS, one of which being helping to shape national policy on important neurological research issues. [1] He received great praise for his time as director from both Harold Varmus, former director of the NIH and current director of the National Cancer Institute (NCI), and Richard Klausner, former director of the NCI. [1] Fischbach left NINDS is 2001 when he was named Columbia University's Vice President for Health and Biomedical Sciences. [1]
While at the NINDS, Fischbach researched the effects of neuregulin, which is a family of proteins including heregulin, neu differentiation factor, ARIA, and glial growth factor that are critical for vertebrate embryogenesis and specifically for the formation of vertebrate spinal cord oligodendrocytes. Fischbach and his colleagues noticed that oligodendrocytes failed to form in mice that were homozygous for the mutant neuregulin gene. However, when wild-type neuregulin was added to homozygous mutant neuregulin explants (isolated tissue cell cultures) nine days after conception of the embryos, normal oligodendrocyte development occurred. This indicated that neuregulin is not necessary for the proliferation of oligodendrocyte multipotent precursor cells. Additionally, when IgB4, a neuregulin inhibitor, is added to wild-type explants, oligodendrocyte development failed to occur. [12]
After serving as the Director of the National Institute of Neurological Disorders and Stroke at the National Institute of Health, Gerald Fischbach was selected as the Vice President and Dean of the Health and Biomedical Sciences, the Dean of the Faculty of Medicine, and the Dean of the Faculty of Health Sciences at Columbia University in New York City. [4] He served as the Dean for all three branches simultaneously. Fischbach was interviewed in 2001 by the newspaper for Columbia University Health Sciences, and there he stated that the mission of the University was "to use all its resources to reduce the burden of human disease." [13] He explained that this required interdisciplinary and collaborative work with the other departments and resources at Columbia University. The Health and Biomedical Sciences division at Columbia University includes the School of Nursing, the Joseph L. Mailman School of Public Health, the School of Dental Medicine, the College of Physicians and Surgeons, and the Audubon Business and Technology Center. The Audubon Center is the only research park that is affiliated with a university in New York City and holds the only incubator for business related to biotechnology. [14]
The research Fischbach conducted at Columbia University stemmed from his previous work at Harvard University, Washington University and with the National Institute of Neurological Disorders and Stroke, National Institute of Health. The specialized focus of his research was on the influence trophic factors could have on the survival of nerve cells and the efficiency of synapses. After his arrival to Columbia, Fischbach was focused on the expression of neuregulin in regards to neuromuscular synapses, signaling pathways in the brain, transcription factors, as well as work on autism. [15] [16] [17] [18] His research on Neuregulin-1 revealed a possible function in CNS neurogenesis since the neuregulins were labeled throughout proliferation with an anti-MAP2 antibody and an anti-nestin antibody were suggested to have become neuron-restricted progenitors. [19] Some of his other research examined the relationship between neuregulin and expression of myosin heavy chain and transcription factors in human muscle. The research found that treatment including neuregulin increased the number of acetylcholine receptors on the surface of the myotube as well as an increase in the early growth response family for transcription factors. These findings impact the available knowledge regarding muscle spindle fiber formation, myosin heavy chains development, and the feasibility of mimicking muscle development processes in vitro. [17]
In 2006, Fischbach joined the Simons Foundation as the scientific director to oversee the Simons Foundation Autism Research Initiative. The Simons Foundation is an organization founded by Jim Simons and his wife Marilyn, and has awarded $130 million for autism research as of 2008. [2] As scientific director, Fischbach collaborates with mathematicians, engineers, chemists, and neuroscientists to try and understand autism more completely. Currently, Fischbach oversees research focusing on the neurobiology of autism and how it can relate to finding a possible cure. [2] [18]
Additionally, Fischbach and his colleagues are working on the Simons Simplex Collection (SSC), which is designed to identify genetic factors that increase the risk of autism. [18] Over 100 researchers and 13 universities have interviewed and collected blood samples from more than 2000 families to look for a genetic linkage to autism. [2] The majority of tested individuals have moderate to severe autistic symptoms and do not display high levels of intellectual disability. Additionally, autistic individuals from enrolled SSC families exhibit genetic deletions, duplications, and copy number variants (CNVs) that are not present in unaffected family members. Siblings serve as ideal control groups to identify unique CNVs associated with autism. Although CNVs are rare and are found in only up to 1% autistic individuals, the presence of multiple CNVs in autistic individuals may account for a larger fraction of autism cases. Ultimately, the goal of the SSC is to expand the number of individuals enrolled in the program in hope of identifying penetrant CNVs, small de novo mutations, and single nucleotide polymorphisms that are linked to a higher risk of autism. [18]
Along with this research, Fischbach and his colleagues at the Simons Foundation are studying diseases that have autistic features, such as Rett syndrome and Fragile X syndrome. The hope is that a better understanding of the central role of the synapse in autistic symptoms can be discovered as well as which specific regions of the brain are responsible for these behaviors. Within the next decade, the ultimate goal of this research is to determine the precise neural circuitry involved in autism and how it translates to the autistic behaviors displayed. [20]
Fischbach has received the following awards: [1]
Fischbach has authored or co-authored over a hundred papers on his research work, which according to the Web of Science have been cited over 10,000 times, giving him an h-index of 57. [23] Some selected publications are:
Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic.
A motor neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectly control effector organs, mainly muscles and glands. There are two types of motor neuron – upper motor neurons and lower motor neurons. Axons from upper motor neurons synapse onto interneurons in the spinal cord and occasionally directly onto lower motor neurons. The axons from the lower motor neurons are efferent nerve fibers that carry signals from the spinal cord to the effectors. Types of lower motor neurons are alpha motor neurons, beta motor neurons, and gamma motor neurons.
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The field of neural development draws on both neuroscience and developmental biology to describe and provide insight into the cellular and molecular mechanisms by which complex nervous systems develop, from nematodes and fruit flies to mammals.
In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the flow of positively charged ions into the postsynaptic cell, is a result of opening ligand-gated ion channels. These are the opposite of inhibitory postsynaptic potentials (IPSPs), which usually result from the flow of negative ions into the cell or positive ions out of the cell. EPSPs can also result from a decrease in outgoing positive charges, while IPSPs are sometimes caused by an increase in positive charge outflow. The flow of ions that causes an EPSP is an excitatory postsynaptic current (EPSC).
A neuromuscular junction is a chemical synapse between a motor neuron and a muscle fiber.
End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.
Synaptogenesis is the formation of synapses between neurons in the nervous system. Although it occurs throughout a healthy person's lifespan, an explosion of synapse formation occurs during early brain development, known as exuberant synaptogenesis. Synaptogenesis is particularly important during an individual's critical period, during which there is a certain degree of synaptic pruning due to competition for neural growth factors by neurons and synapses. Processes that are not used, or inhibited during their critical period will fail to develop normally later on in life.
In cellular neuroscience, the soma, perikaryon, neurocyton, or cell body is the bulbous, non-process portion of a neuron or other brain cell type, containing the cell nucleus. Although it is often used to refer to neurons, it can also refer to other cell types as well, including astrocytes, oligodendrocytes, and microglia. There are many different specialized types of neurons, and their sizes vary from as small as about 5 micrometres to over 10 millimetres for some of the smallest and largest neurons of invertebrates, respectively.
Jean-Pierre Changeux is a French neuroscientist known for his research in several fields of biology, from the structure and function of proteins, to the early development of the nervous system up to cognitive functions. Although being famous in biological sciences for the MWC model, the identification and purification of the nicotinic acetylcholine receptor and the theory of epigenesis by synapse selection are also notable scientific achievements. Changeux is known by the non-scientific public for his ideas regarding the connection between mind and physical brain. As put forth in his book, Conversations on Mind, Matter and Mathematics, Changeux strongly supports the view that the nervous system functions in a projective rather than reactive style and that interaction with the environment, rather than being instructive, results in the selection amongst a diversity of preexisting internal representations.
Neuregulins are a family of four structurally related proteins that are part of the EGF family of proteins. These proteins have been shown to have diverse functions in the development of the nervous system and play multiple essential roles in vertebrate embryogenesis including: cardiac development, Schwann cell and oligodendrocyte differentiation, some aspects of neuronal development, as well as the formation of neuromuscular synapses.
MuSK is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin, which is similarly also required for neuromuscular junction formation.
A neuromuscular disease is any disease affecting the peripheral nervous system (PNS), the neuromuscular junctions, or skeletal muscles, all of which are components of the motor unit. Damage to any of these structures can cause muscle atrophy and weakness. Issues with sensation can also occur.
Alpha (α) motor neurons (also called alpha motoneurons), are large, multipolar lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for initiating their contraction. Alpha motor neurons are distinct from gamma motor neurons, which innervate intrafusal muscle fibers of muscle spindles.
Dok-7 is a non-catalytic cytoplasmic adaptor protein that is expressed specifically in muscle and is essential for the formation of neuromuscular synapses. Further, Dok-7 contains pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domains that are critical for Dok-7 function. Finally, mutations in Dok-7 are commonly found in patients with limb-girdle congenital myasthenia.
Neuregulin 1, or NRG1, is a gene of the epidermal growth factor family that in humans is encoded by the NRG1 gene. NRG1 is one of four proteins in the neuregulin family that act on the EGFR family of receptors. Neuregulin 1 is produced in numerous isoforms by alternative splicing, which allows it to perform a wide variety of functions. It is essential for the normal development of the nervous system and the heart.
43 kDa receptor-associated protein of the synapse (rapsyn) is a protein that in humans is encoded by the RAPSN gene.
Neuromuscular junction disease is a medical condition where the normal conduction through the neuromuscular junction fails to function correctly.
Neuregulin 3, also known as NRG3, is a neural-enriched member of the neuregulin protein family which in humans is encoded by the NRG3 gene. The NRGs are a group of signaling proteins part of the superfamily of epidermal growth factor, EGF like polypeptide growth factor. These groups of proteins possess an 'EGF-like domain' that consists of six cysteine residues and three disulfide bridges predicted by the consensus sequence of the cysteine residues.
Thomas Christian Südhof, ForMemRS, is a German-American biochemist known for his study of synaptic transmission. Currently, he is a professor in the school of medicine in the department of molecular and cellular physiology, and by courtesy in neurology, and in psychiatry and behavioral sciences at Stanford University.
David S. Bredt is an American molecular neuroscientist.