Men ought to know that from nothing else but the brain come joys, delights, laughter and sports, and sorrows, griefs, despondency, and lamentations. And by this, in an especial manner, we acquire wisdom and knowledge, and see and hear, and know what are foul and what are fair, what are bad and what are good, what are sweet, and what unsavory… And by the same organ we become mad and delirious, and fears and terrors assail us … All these things we endure from the brain, when it is not healthy… In these ways I am of the opinion that the brain exercises the greatest power in the man.
On the Sacred Disease, Hippocrates, 400 B.C.
The Brain and the Nervous System
The most complex device in the known universe is the human brain. Its hundred billion neurons (nerve cells) are connected via trillions of synapses (junctions). Its principal structures and connections are largely assembled during pregnancy, from conception to birth, and refined over the subsequent twenty years of life. The brain is an essential organ of the body, because the slightest defects in its functions prevent us from using the others properly, even if those are healthy.
The connection between the brain and the rest of the body is provided by the nervous system. The nervous system is of unique importance: joints, kidneys and even hearts can be bypassed or replaced without altering a person in fundamental ways, but the essence of a person is lost when the activity of the nervous system ceases – fundamentally human. This makes the nervous system a source of endless fascination. The nervous system has two main divisions: the central nervous system (CNS), consisting of the brain and the spinal cord, and the peripheral nervous system (PNS), consisting of the nerves and nerve cells that lie outside the brain and the spinal cord. The functional units of the nervous system are the neurons; the neuron receives, processes and disseminates information over a considerable distance. These specialized functions of the neuron have endowed it with a characteristic shape; it consists of a cell body, surrounded by two types of arms (dendrites and axons), that can extend for a meter or more. Dendrites receive information coming into the cell body and the axon transmits the resultant signals to other neurons or muscles; each neuron receives information from thousands of other neurons and passes this information onto thousands of others. This complex network allows the redistribution of information to different parts of the CNS and to the muscles via the PNS, relayed both in electrical and chemical ways.
The U.S. Congress and the National Institutes of Health (NIH) announced the 1990s as the “decade of the brain,” in order to enhance research in neurosciences and to encourage scientists working in brain research. The goal of neuroscience is to understand how the nervous system functions. Although the historical foundations of neuroscience were established by many people in many generations, research into brain and behaviour is relatively new and has emerged as a clear and distinct discipline in the last 30 years, becoming one of the fastest-growing areas of modern biology. Neuroscience is multidisciplinary and contributions are generated in many fields such as biochemistry, molecular biology, cell biology, genetics, neurology, physiology, anatomy, psychology and clinical medicine.
Neuroscientific research can be classified at different levels, in order of complexity: molecular neuroscience examines the brain and the nervous system at its most elementary level, using molecular biology, molecular genetic and protein chemistry tools; cellular neuroscience focuses on the molecules which give neurons their morphology and physiological properties; developmental neuroscience studies the processes that generate, shape and reshape the nervous system and tries to understand the cellular basis of neural development; systems neuroscience analyzes complex neural circuits that perform a common function; behavioural neuroscience investigates the functioning of neural systems to produce integrated behaviours, and cognitive neuroscience investigates neural mechanisms responsible for the higher levels of human mental activity.
In recent years neurodegenerative diseases, which pose a major burden on modern society have become an emerging and challenging research focus of neuroscience. Neurodegeneration (malfunctioning of nerve cells) is the terminology used for pathological conditions progressively affecting neurons in different regions of the brain and the CNS. More explicitely, it is the process in which neurons in different regions of the CNS lose their normal functions or structures and eventually end up dying. To compare neurodegeneration with cancer, another public health challenge in developed countries: cancer is the result of uncontrolled proliferation of cells, whereas neurodegeneration is the result of uncontrolled degeneration and death of cells. Neurodegenerative diseases represent a large group of progressive neurological disorders with heterogeneous clinical and pathological manifestations. The most common representatives are Alzheimer’s and Parkinson’s Diseases (AD and PD), followed by Huntington’s Disease (HD), Friedreich and spinocerebellar ataxias (FRDA, SCAs) and amyotrophic lateral sclerosis (ALS). Some of these diseases result primarily in impairment of major mental qualities, whereas some others lead to deterioration of physical activites and vital functions, including respiration, swallowing, balance, movement and heart function. These manifestations may strikingly overlap in different conditions, thus the differential diagnosis of neurodegenerative diseases may sometimes be very complicated. Consistent risk factors for developing neurodegenerative disease are genetic background, environmental and dietary factors and most importantly aging. Since today the growth rate of the population aged 65 and beyond is very high in developed countries, it can be anticipated that, over the next generations, the proportion of elderly citizens will double, thus increasing the proportion of persons suffering from some kind of neurodegenerative disease.
Neuroscience in the Genomics Era
The molecular biology revolution allowed neuroscientists to move from the study of circuits and systems to the detailed study of individual molecules. However, moving from analysis at the genetic level to an understanding of interacting signalling or metabolic pathways poses enormous challenges; combining these data to achieve a systems-level understanding of brain circuit function in health and disease is even more demanding. The extreme cellular heterogeneity and complexity of neural circuits, as compared to most non-neuronal tissues, require the integration of powerful methods, like computational biology, genomic advances and rapidly evolving laboratory technologies. Luckily, we are in the middle of a genomics and informatics revolution, which permits us to benefit from the power of large-scale genetic, genomic and phenotypic data sets, produced in high-throughput (effective, large-scale) genome laboratories, and to harness the development of tools for data mining and integration. The so-called ‘omics’ research requires not only large-scale instrumentation, but also multidisciplinary teams of biologists, neurologists, computer scientists, mathematicians and statisticians. Genetic and functional genomic studies have already yielded important insights into neuronal diversity and function, as well as disease. The pace of neuroscience research today is breathtaking and raises hopes that soon we will have new treatments for the wide range of nervous system disorders.
New Frontiers in Neurodegenerative Disease Research
Diseases of the CNS are the end products of a complex genetic and regulatory network and still remain among the most challenging disorders known to mankind. This is because neurological disorders are typically devastating not only to affected patients, but also to their families, often robbing individuals of the qualities that we most strongly associate with being human. Furthermore, the majority of neurological and neurodegenerative disorders lack effective therapies. Completion of the human genome project paved the way for great advances in our understanding of the pathogenic basis for several disorders, and taught us also that common diseases, like cardiovascular disease, stroke, cancer and neurodegenerative/mental brain diseases have a strong genetic component, with a complex inheritance pattern. Today, in the genomics era, the scientific landscape has changed drastically. The complexity of the nervous system and the complex genetics of neurological disorders make functional studies in neurosciences essential and vital. Most of the diseases can be faithfully and reliably mimicked in cell cultures and model organisms. The study of neurodegenerative diseases has benefited greatly from genetic models that are based on inherited mutations in disease-associated genes. An important aspect of this research is the finding that similar mechanisms, common for all diseases, operate in neuron degeneration and loss, despite selective neuronal death in different brain regions. Thus, it becomes more meaningful to classify neurodegenerative diseases by their molecular characteristics, rather than by their clino-pathological symptoms, and to redefine the diseases as the consequence of biochemical processes, which overlap in many of these diseases. The last few years witnessed a series of unexpected developments that have refocused the field upon new paradigms, eg, protein aggregation, a common cellular hallmark of many neurodegenerative diseases, which plays a pathogenic role in neuron degeneration; the signature of mitochondrial defects as a potential deleterious mechanism in neurodegenerative processes; the many lines of evidences supporting a role of oxidative and nitrative stress; axonal transport defects; the striking importance of non-neuronal cells in ALS, and last but not least, altered RNA processing in several neurodegenerative diseases. These mechanisms are still elusive and translation of this research into therapies in humans has been more complicated than initially anticipated.
Conclusion: Where are we?
A complete picture of the molecular architecture of neurological diseases can only be achieved by a thorough functional understanding of the versatile novel mechanisms leading to neuronal death. Despite great advances in the field of neurobiology, along with the state-of-the-art technological assays and innovative model systems developed in recent years, our knowledge of the cellular pathways leading to human brain diseases is unfortunately still limited, because the CNS is an organ of unparalleled cellular complexity and access to human nerve cells is restricted.
Difficulties encountered in dissecting neurological processes hopefully will soon be overcome thanks to continiuously emerging recent advances in cell biology; thus we have today several reasons to be optimistic. Among many others, stem cell research has gained a great attraction (ES: embronic stem cells or iPS: induced pluripotent stem cells). Stem cells share the ability to self-renew indefinitely and have the potential to differentiate into all cell types. Stem cell technologies are an especially promising but also a challenging research field; promising, because stem cells have a high therapeutic potential and can be used to replace affected and dying neurons; challenging, because the functional integration of stem cells into the brain circuitry may prove very intricate. But independent of their therapeutic potential, stem cells also offer a very high-powered tool for research; by deriving iPS cells directly from somatic cells of patients with different neurological disorders, they can be used to model neurological diseases. This opens up an invaluable opportunity to investigate disease mechanisms and to search for new drugs in human disease-specific cell lines. Most importantly, this approach will avoid potential differences between animal models and human neurons which seem to be a major obstacle in human clinical trials; moreover patient-derived iPS cells may be used to develop patient-specific drugs tailored for a particular genetic and clinical background. The strongest driving force and the ultimate goal in stem cell research is the regeneration of damaged neurons and repair of neural networks. Although restorative neurobiology is, without doubt, the most efficient therapeutic application of pluripotent stem cells, the time for its routine use in humans has not come yet. Today, the greatest impact of stem cell biology lies in its powerful application in modeling and dissecting the molecular and cellular basis of neurodegenerative processes; this will eventually open new therapeutic avenues and pave the ways for long-awaited therapies.
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