If you have ever looked at American paintings from the late 18^th and early 19^th centuries, one common and striking characteristic is almost always present. The children in the group portraits, a favorite of these Primitive painters, are small adults or grown-ups shrunk to about half size. Some of the little boys even appear to have five-o’clock shadows.

The view that children were just adults writ small remained pervasive for many years in general culture — and in medical and behavioral research. That time has passed, both in the general outlook and among medical researchers. We accept that children are not small adults, but young and developing human beings, with particular physiological and emotional characteristics, requirements, expectations, and needs.

A better way of looking at children comes from about the same time, around two centuries ago, in a familiar line from the poet William Wordsworth: "the child is the father of the man." Of course, today we hasten to add that the child is also the mother of the woman. That is, the child is the physical and emotional antecedent of the adult that child will one day be.

Or perhaps not be, but rather become. The genetic and environmental influences in the course of a child’s development do not come, of course, all at once. Genes may express themselves at different times in different ways, and other physiological events, like puberty or serious illness, can also have lasting effects for better or worse — that is the nature of nature. In the same way, the environment in which the child lives is undergoing constant change, sometimes again for better or worse, with lasting influence on the child’s emotional development — and that is the nature of nurture.

Consequently, when the NIH — when all the Institutes and Centers that make up the NIH and support and conduct research — look at children, we certainly give great thought and care to the diagnosis, prevention, and treatment of diseases that afflict them especially. There is, I suppose, a deep and primal pang we feel in the presence of a sick child or even when we hear about sick children. It may be one of those evolutionary mechanisms that has enabled our species to thrive.

But when we look at children, we also see something else and something of great importance. We see children’s health and the natural healthiness of children. This leads us into inquiries into the biomedical and behavioral mechanisms and influences that enable children to grow normally, to learn, to acquire the social, emotional, and intellectual readiness for school and friendships, for responsibility, for real intellectual engagement with logic, for example, or mathematics, and finally for work and for being parents of their own children.

A greater understanding of normal, healthy development will show us new ways to promote better health in children — and, therefore, in the adults they will become. Such an understanding will also sharpen our searches into the causes of sickness in children and lead to better medical and behavioral interventions and preventions. And so, NIH studies good health and sickness, by supporting and conducting a range of studies from the clinical to laboratory research. But it is through basic research that we acquire the most profound and propelling insights into health.

And given the focus of our program today, I think it’s apt to start with an example of research on the brain. Nature wraps the brain in a substance like leather, bathes it in fluid, and encases it in a hard package of bone. Good protection, but it has until recently made the study of the brain difficult, and the radiation of x-rays and CT scans precluded their use in studies of healthy children.

Magnetic Resonance Imaging — the MRI — has altered that. NIH Investigators have made a remarkable discovery using MRIs. We have known for years that brain development begins with over-production of brain cells and connections, followed by a competitive process in which they are Apruned" away. We also thought we knew that this process occurred during pregnancy or perhaps in the first 18 months of life. That is not so. MRI images of healthy youngsters taken every two years have shown that there is a second round of brain-cell over-production, peaking on average at 11 for girls and 12 for boys, around the time of puberty, followed again by a second pruning of the excess.

Why this happens is still unknown, but one hypothesis is that the brain is pruned according to a Ause it or lose it" principle. Thus, a teenager who uses the brain cells involved in judgment and organization will keep those and lose others while another who uses drugs and alcohol as the pruning is going on may suffer some bad consequences. This gives us a physiological, rather than a moral or social, reason for avoiding risky behavior. The same researchers have also reported that, in childhood schizophrenia, the pruning of new cells may be four times the normal rate in the frontal area of the brain. Why this should be and what prevention is possible we cannot tell. But this new knowledge points the way to promising new research on childhood mental illness.

Other NIH research, on Attention Deficit Hyperactivity Disorder or ADHD, also holds much promise. MRI imaging of youngsters with ADHD revealed, as one investigator memorably put it, that "the brain is not broken." But the images they have taken have revealed a small but distinct difference in the sizes of the brains of children with ADHD — a difference of between five and 10 percent, specifically in the frontal lobe, the basal ganglia, and the cerebellum. These findings are significant since these areas of the brain control functions, like cognition and movement, that are out of kilter in ADHD. These areas are also rich in dopamine, a neurotransmitter, which likewise has a role in cognition and movement. A preliminary conclusion is that smaller dopamine regions yield fewer dopamine circuits firing fewer functions that depend on dopamine for normal health. This, of course, is not yet conclusive, but again it is putting us on the track of new discoveries for clinical therapies and interventions.

Any track that leads us to new therapies for children with mental illness is worth following, even if that track seems at first to lead toward human adults — or songbirds. The growth of brain cells during life is called neurogenesis. We had believed that it was a phenomenon early in life. As I have said, we have learned from basic research that it continues until puberty. And we have also learned from further basic research that it continues into adulthood. This knowledge came from basic research on songbirds when researchers discovered the number of neurons increased and decreased in the course of the mating season. And it rekindled interest in studying higher animal models, beginning with rodents, then monkeys, and finally humans, resulting in the discovery of neurogenesis of the hippocampus in late adolescents and even in adults.

More research is finding that the rate at which new neurons are produced can be influenced by environmental factors, particularly stress, which inhibits the formation of new neurons. These discoveries are opening the way to future interventions to deal with brain loss after stroke or trauma — and also to autism, which usually strikes the very young, and to schizophrenia, which often has its onset in adolescence. It also may be that decreases in neurogenesis in the hippocampus may be a factor in causing depression, which, as you know, is a growing and terribly troubling affliction among the young. So it may be possible that neurotransmitters that stimulate neurogenesis in the hippocampus may be used to treat depression.

The hippocampus is also, we know, important for learning and acquiring memories. NIH researchers have discovered a gene that controls the development of the hippocampus, a discovery that provides valuable insight into understanding the development of the brain. I said a while ago that our interests are in understanding good health and in fighting disease. A discovery like this one enables us to do both. It gives us insight into the processes that lead to development of a normally functioning hippocampus. And, since problems in the hippocampus may be related to depression, ADHD, and possibly schizophrenia, this discovery also gives us fresh guidance in dealing with these illnesses that afflict the young.

And let me state again that the young are not just short adults. We are painfully aware that we know less about the young brain and mental disorders of the young than we do about the adult brain and adult mental illness. But, as one of my colleagues eloquently said, "it is what we don’t know that beckons us on in our research." And so we are proceeding. We have come to understand, in brain development and in vulnerability to mental disorders, that gene-to-gene interactions do not explain everything. Gene-to-environment interactions are equally complex, and thus present equal opportunities for discovery.

We understand that the environment — in other words, experience — produces biochemical changes in the cells of our brains. We refer to this as "brain plasticity." As experiences, especially in the early years of development, mount up, they begin to "sculpt" the brain — that is, the environment regulates the genes, building new connections, like memories or skills. Animal studies have shown us that when the young are handled — simply, touched in a maternal way — they had reduced hormonal responses to stress compared to other young animals that were not fondled. Their hippocampi have more receptors for the hormone that is secreted during stress, cortisol, and can clamp down on its production more rapidly. And this reduced response to stress lasted their entire lives.

Behavior, of course, exists at that complex intersection of genes and environment, of nature and nurture. That is why dealing with emotional disorders is so much more difficult, and even resistant, than dealing with physiological problems. Let me give you an example. Haemophilus influenzae Type 2 — called Hib — used to cause about 20,000 cases a year of bacterial meningitis yearly. It is one of the serious complications of Hib, occurs in 60 percent of the affected children, and can cause mental retardation. Since NIH researchers developed a vaccine for Hib in the 1980s, the number of cases of bacterial meningitis has declined to fewer than 100 a year.

If only we had a vaccine for risky behavior. We do not, but we do have NIH behavioral research, which is identifying and providing insights into the influence of family, peers, neighborhoods, schools, and general culture on the choices young people make, for example, in their health behavior. Recent declines in smoking and drug use seem to reinforce our belief that the right messages will have the right influence. And this line of inquiry may prove valuable in withstanding the other emotional, behavioral, and social problems young people encounter.

We also have the basic research, some of which I have been describing, that provides the greater understanding of the complementary effects of genes and environment on the development of the brain and on mental and emotional disorders. While we do not know as much as we need and want to, we do know more and more about the young. All across the NIH, the Institutes and Centers are adding to our knowledge, giving us more insights, opening more promising opportunities for medical and behavioral research, and fueling us with the optimism that we can learn more about the nature of good health and about prevention and therapy for disease and disorders. That is where what we do not know — but are determined to know — beckons us.