INTRODUCTION - 2006 Progress Report on Brain Research

by Thomas R. Insel

January, 2006

Winston Churchill is usually considered the source of the aphorism that we make a living from what we get and we make a life from what we give. Whoever is the source, the sentiment is as relevant to science as it is to individuals. In neuroscience, while much attention this year has been focused on “making a living,” the field is clearly “making a life,” as we are giving more to society than ever. This Progress Report documents many of the areas where remarkable advances were reported in 2005. In truth, the report provides only a sampling. A comprehensive description of progress in neuroscience would need to be at least 10 times longer, even if limited to reports from 2005.

What is apparent in every part of this Progress Report is that neuroscience is providing critical insights about the brain. In the best sense, this is science for public health. The need is certainly urgent. The more than 1,000 disorders of the nervous system result in more hospitalization than any other disease group, including heart disease and cancer. Stroke is one of the three greatest medical sources of mortality, depression causes the greatest disability for adults under age 45, and suicides continue to outnumber homicides by almost two to one. The aging of our population makes Alzheimer’s and other neurodegenerative diseases an increasing public health priority. And, at the other end of the life span, the prevalence of autism spectrum disorders has now been estimated at 1 in 166 births, roughly a tenfold increase in the past decade.

The good news is that we have extraordinary new tools and technologies with which to address these urgent public health challenges. The results from these advances are evident throughout this report, but their development deserves recognition as a keystone of progress.

The Human Genome Project, which was published with great fanfare in 2003 (on the 50th anniversary of the publication of the original double helix paper by James Watson and Francis Crick), provided a consensus map of human DNA, but it failed to describe variation. Because variation is the key to understanding individual vulnerability and resistance to disease as well as human diversity, a map of human DNA variation may be even more informative than the original consensus map.

This year marks the completion of the “HapMap” project, the first comprehensive map of human haplotypes, which mark the millions of single points of variation in our genomes.1 With the HapMap and new chips for mapping variation, genetics has become markedly cheaper and faster just in the past year. The question of how individual variation in DNA sequence is associated with risk for disease can now be answered not only for single-gene diseases (such as Huntington’s disease), but also for complex genetic diseases. In the past year, scientists have used the power of this whole-genome approach to identify genomic variations that confer risk for Parkinson’s disease and age-related macular degeneration, changing our understanding of these disorders.2,3 In the next few months, we are hopeful that studies using the HapMap and new genomic technologies will provide similar insights for a range of nervous system disorders from autism to Alzheimer’s.

Neuroimaging, discussed in detail by Marcus Raichle, also has given us a new perspective on the brain. Research in 2005 included remarkable advances in our ability to visualize individual cells, even in the living brain. In addition, both structural and functional studies of the whole brain have been enhanced to allow neuroscientists to identify pathways for information in the brain. With imaging we can map the remarkable plasticity in the human cortex, 4 the circuits for processing faces and language, 5 and even the evidence for information that is encoded without any conscious awareness.6

In ways that we may never have imagined, our brain anatomy appears to be determined by our genes, with differences in genetic sequence coding for very specific individual differences in brain structure and function.7 As one reads the several sections in this report that describe various insights from neuroimaging, it is striking how the brain is organized in ways that we find counterintuitive. Indeed, the closer we get to mapping the circuitry for emotion or consciousness, for example, the more mysterious (and complex) these mental processes appear.

Stem cell technology also provides a powerful tool for the researcher interested in how genetic variation or environmental factors alter the fate of a developing neuron.

Perhaps no area has held more surprises than stem cells. Although we might have expected neurons to be among the most complex adult cells to derive from stem cells, neurons have proved to be among the easiest cells to grow. As described in this report, in 2005 neuroscience made great strides identifying the developmental steps required to grow a neuron from the least developed precursor cell. The importance of this research for neurodegenerative diseases is obvious; stem cell biology has given birth to the entirely new field of regenerative medicine. Less appreciated but no less important, stem cell technology provides a powerful tool for the researcher interested in how genetic variation or environmental factors alter the fate of a developing neuron.8 For the first time, we can study both nature and nurture at the cellular level.

The challenge in all of these areas—genomics, imaging, stem cell biology—is to translate the technological advances into improved public health and welfare. Each of these advances can be a powerful force for improving health care, but each can be used to perpetuate injustice. The emerging field of neuroethics has begun to grapple with the thorny questions of how we ensure that neuroimaging is not used for “mind reading” or that genomics is not used to preclude health insurance. While some of the concerns are based on a fantasy of what the technology can do (current neuroimaging has limited use for “mind reading,” and genomic assessment of disease risk is largely statistical), neuroscientists are increasingly thinking into the future to consider how the power of this science can be used for the greatest public good, as described in this report.

I began this essay by noting that scientists “make a life” by what they give. Since the beginning of 2005, neuroscientists have begun to join forces to try to give more. The Neuroscience Blueprint at the National Institutes of Health (NIH) is an excellent example.9 Analogous to the NIH Roadmap, which is designed to overcome obstacles to progress in medicine, the Neuroscience Blueprint is a multi-institute effort to address the big challenges in understanding the nervous system in health and disease. The Blueprint has already prompted new training programs on the neurobiology of disease, expanded collaborative efforts in neurogenomics and pediatric neuroimaging, and created a forum for all NIH institutes with an interest in neuroscience to work together. Projects in the next year include the development of transgenic mouse lines for neuroscience, training programs in neuroimaging, and the development of multi-institute core resources for scientists at universities.

The 1990s were labeled the “Decade of the Brain.” The current decade may, in retrospect, appear to be the “Decade of Discovery,” with most of the major genes and proteins and pathways for brain function identified for the first time. This report, near the midpoint in this decade, attests to the excitement of this period in neuroscience research as we begin to map the intricacies of the body’s most complex organ. Increasingly, the discoveries from basic neuroscience are being translated into insights for public health, yielding new approaches to diseases as diverse as Alzheimer’s, autism, and drug addiction.

For those with a nervous system disease, research is hope. There has never been a time to be more hopeful.