By David C. Van Essen, Ph.D.
President, Society for Neuroscience
This year’s Progress Report summarizes more than 100 research discoveries that collectively illustrate how research in neuroscience is helping to better understand, diagnose, and treat many debilitating diseases and disorders of the nervous system. Each of the 10 sections focuses on discoveries related to a particular class of disorders or to a cross-cutting theme such as neuroethics. These individual discoveries (“nuggets of neuroscience”), and the broader themes that emerge from the report as a whole, are a significant part of the grand quest to understand the human brain in health and disease.
The human brain is an amazingly complex structure for processing information and controlling all aspects of our behavior. The complexity of the brain’s intricate neural circuitry, involving billions of neurons and trillions of synapses, greatly exceeds that of any other organ system in the body.
This complexity is evident at many levels. At molecular and cellular levels it involves exquisitely choreographed molecular signals for transmitting information from one cell to another and for adjusting the strength of these signals during development and learning. At the systems level, it involves a symphony of coordinated neural activity patterns involving thousands of distinct brain structures communicating through tens of thousands of anatomical pathways. It also involves a high degree of individual variability in brain structure and function from one person to the next that is responsible for the tremendous diversity in our individual personalities and intellectual capabilities.
Given the brain’s staggering complexity—far greater than that of a space shuttle or a supercomputer—it is hardly surprising that the nervous system can malfunction in countless ways. Indeed, more than 1,000 disorders and diseases of the nervous system have been identified, and the list continues to grow. The most prevalent afflictions, including Alzheimer’s, schizophrenia, stroke, and learning disabilities, in aggregate affect a large fraction of our population and place a staggering burden on society in terms of economic impact, distress, and human suffering.
Without major progress in preventing and treating nervous system disorders, this burden will only grow as people continue to live longer. In order to accelerate progress, we need a much deeper understanding of disease mechanisms and of the normal mechanisms of brain function and brain plasticity, or adaptability. Such advances, including those highlighted in this report, will allow us to better harness and enhance the normal capacity of the nervous system to regenerate, repair, and adapt itself to insult and injury.
Several broad themes emerge from accomplishments in brain research in 2006. One involves progress in characterizing the genetic factors contributing to a variety of neurological and psychiatric disorders. These range from the elucidation of the role played by specific genes in familial Parkinson’s disease to the identification of many anxiety-related genes in a mouse model.
Another powerful strategy is to combine what we know of a gene with other experimental approaches such as neuroimaging. An exciting example in this report involves using magnetic resonance imaging to characterize brain abnormalities (in both structure and function) in individuals who carry a particular genetic variation implicated in violent behavior but who have no history of psychiatric disorder.4 The power of neuroimaging approaches is also evident from discoveries of distinct brain structural abnormalities in attention-deficit/hyperactivity disorder and functional abnormalities in autism.
Neurodegenerative diseases, including Parkinson’s disease, Huntington’s disease, Alzheimer’s, and amyotrophic lateral sclerosis (ALS), continue to be the focus of intensive investigation in many laboratories. One set of advances involves a better understanding of the cell biology of how some proteins fail to fold into molecular configurations that make them function properly and how the normal machinery for coping with misfolded proteins may cause degeneration when it goes awry. Another approach to the problem is to use interventional strategies to deliver treatments that protect against neuronal damage and death.
Other research continues to reveal the role of the immune system in relation to the brain. Normally the two “play well together,” but many discoveries this past year point to the devastation that can occur when the immune system is provoked to attack the brain. One arena involves inflammatory responses that aggravate the neuronal damage initiated by neurodegenerative processes in Alzheimer’s, Parkinson’s, Huntington’s, and ALS. These discoveries have led to new therapeutic strategies involving anti-inflammatory drugs to reduce neuronal damage in each of these neurodegenerative diseases.
In autoimmune diseases such as multiple sclerosis, the attack by the immune system appears to be a primary assault directly on glial cells. Discoveries in the past year have provided important insights regarding the identity of key proteins that mediate the immune attack and the identification of an antibody biomarker that may allow better regulation of certain treatments in autoimmune diseases.
In the human brain, neurons that die are irreplaceable, insofar as the birth of new neurons (neurogenesis) does not occur in adults except in restricted brain regions. The prospect of instituting neuronal replacement therapy has been something of a holy grail for many neuroscientists, especially because adult neurogenesis is widespread in many other species. Hair cells in the ears’ cochlea are a particularly attractive target because they are part of a relatively simple neural circuit and because hearing loss is such a prevalent and debilitating disorder. Recent progress in characterizing genes that regulate hair cell proliferation provide hope for future progress.Elsewhere in the brain, intensive efforts are under way to determine what regulates neurogenesis in the hippocampus and other brain regions where it takes place and to use stem cells to promote useful neurogenesis in other regions of the brain and spinal cord.
An overarching theme is that progress in diagnosing and treating brain-related diseases also can bring special challenges that have implications for ethics and health policy. Members of the Dana Alliance for Brain Initiatives have played a major role in shaping the emergent field of neuroethics. The essay on neuroethics by Steven Hyman provides a thoughtful overview of the history of this new field and of the types of issues it wrestles with. These are brought into sharper focus in the Neuroethics section of the main report, which highlights a range of issues and controversies, including topics related to brain privacy, the nonconscious brain, and the implications of neural prostheses.
Where will brain research go from here? Three clear trends will strongly influence the field well into the future:
Technology drives discovery. Most of the discoveries reported here simply could not have been made a decade ago, because key experimental methods such as functional magnetic resonance imaging and high-throughput gene sequencing were either nonexistent or inadequate. A wide variety of methods for acquiring and analyzing information about the brain are continually being developed by methods-oriented scientists and engineers in academia and in the private sector. Sustained investment in these the efforts is critical for insuring that the pace of discovery continues to accelerate.
Bench to bedside to bench. “Bench to bedside” is a widely used shorthand term for the process of translating discoveries made by basic and translational neuroscientists into improved clinical care. Information flow in the reverse direction, from the clinical side back to basic neuroscience, is now recognized as very important as well. By studying diseases and disease mechanisms, neuroscientists often gain insights into fundamental mechanisms of brain function and development. For example, at all four Presidential Lectures at the 2006 annual meeting of the Society for Neuroscience, the presenters discussed how their own research benefited from bi-directional interactions between basic and clinical neuroscience.
At a personal level, this perspective resonates very strongly because it reflects recent changes in my own research program. Whereas I was a “pure” basic neuroscientist until a few years ago, the main thrust of research in my laboratory currently focuses on specific neurological or psychiatric disorders, using novel methods for analyzing the structure and function of cerebral cortex. On a larger scale, the fastest-growing research theme at the Society for Neuroscience annual meeting is the disease theme, indicating increasing engagement on disease-related research by the neuroscience community as a whole.
The information explosion. The studies described in this report represent the tip of a vast and rapidly expanding iceberg of information that emerges from the neuroscience community each year. Only a fraction of the potentially useful information is published or made accessible in databases. Moreover, even that which is accessible in online journals and databases cannot be searched as easily and effectively as is desirable. This is likely to change dramatically in the coming decade as improvements in information technology open up new vistas that allow scientists, clinicians, and the lay public to access a wealth of information about the nervous system quickly, reliably, and conveniently in ways that we currently can only dream about.