Fifty years later, psychiatry in the United States has been turned upside down. The discovery of psychotropic drugs has transmuted psychiatrists into psychopharmacologists. Despite extensive evidence that manualized psychotherapies (cognitive behavior therapy and interpersonal psychotherapy) are as effective as tricyclics and selective serotonin reuptake inhibitors for mild and moderate depression, interest in psychological treatments continues to wane.

Prodigious advances in neuroscience and in brain imaging have yielded a dynamic model of a brain that is shaped by experience and continues to change over the life course. To cap the revolution, the mapping of the human genome promises to make it possible to identify genes that influence risk and resistance to psychiatric disorders. Discoveries in neuroscience and genomics continue the reshaping of psychiatry into a disproportionately biological specialty where it had once been a disproportionately psychosocial specialty.

Will detailed knowledge of the genome foretell the future of our children? In Greek mythology, three figures wove the tapestry of human fate: Lachesis, the measurer, allotted to each his portion; Clotho, the spinner, spun out the threads of life; and Atropos, the lady of the shears, severed the thread at the appointed time. Similar myths abound in other cultures. In the Icelandic sagas, man's fate is determined by the witches, Urdur, Verdandi and Skuld. How far do these ancient myths foretell the truth? Are adenine, cytosine, guanine and thymine the weavers of our fate?

To put the question in these terms is to enthrone Galton's jingle. To ask how much of the phenotype is due to nature and how much to nurture is as profitless as to ask how much of the area of a rectangle is due to its length and how much to its width. Every phenotypic trait reflects the outcome of gene expression in particular environments.

The impact of neighbors and neighborhood as niche is clearly evident in the findings of the Project on Human Development in Chicago Neighborhoods (5). Tony Earls and his colleagues (6) knew that certain characteristics of neighborhood structure - the concentration of poverty, the extent of ghettoization, residential instability - account for a significant amount of the variance in adolescent antisocial behavior (7). However, what they were able to show by the use of sophisticated statistical methods is that, after adjusting for prior levels of neighborhood crime, informal social control emerged as a significant deterrent to adolescent delinquency (8). "Informal social control" refers to the likelihood that adults in the community will monitor spontaneous children's play groups, intervene to prevent truancy and street corner hanging out by teenagers, and confront persons misusing or disturbing public space. Further, informal social control reflects the ability of cohesive communities to demand needed resources from city authorities for police patrols, fire stations, garbage collection and housing code enforcement. The importance of this power is apparent from the correlation between abandoned housing, burned out buildings, graffiti and litter in an area and more serious crime.

When phenocopies abound, heritability will be low or unmeasurable in such circumstances. Gene effects may become evident only after environmental variance has diminished. When changes in the environment diminish the extrinsic causes of a disease without eliminating that disease altogether, the remaining cases will show a larger heritability (10). Secular changes in the epidemiology of rickets offer a telling example.

Rickets was endemic in the United States in the 1920s. The discovery of vitamin D and the provision of D-enriched milk resulted in a dramatic decrease in the prevalence of rickets. Thus, Albright and his colleagues (11) first reported D-resistant rickets in 1937, the genetic signals previously having been unrecognizable amidst the environmental noise resulting from phenocopies. As improved living conditions in industrialized countries removed exogenous causes, the heritability of rickets increased - from undetectable levels toward one! Yet, exogenous rickets persists, albeit at a low rate, among such populations as Muslim women who continue to cover almost all their skin surfaces with clothing after moving to countries in the Northern hemisphere with less ambient sunlight; and homebound elderly patients in Boston and Edmonton during winter months when atmospheric attenuation of ultraviolet radiation in the 290-315 nm band limits vitamin D3 synthesis in the skin (12,13).

Although the "heritability" of height approaches 0.9, adult height in industrialized countries has increased by several inches during the last two centuries without significant perturbations in the distribution of the genes. Better nutrition and better health have allowed fuller expression of the growth potential already inherent in the genome. In contrast, malnourished children are stunted in growth; computed "heritability" in impoverished families is much lower.

If malnutrition influences the apparent "heritability" of height, what impact does socioeconomic deprivation have on the "heritability" of intelligence? The complexity of the relationship has been clarified in a recent study by Eric Turkheimer and his colleagues (14). They analyzed intelligence test scores on a sample of 320 7-year old twin pairs, one third monozygotic. Their sample was unusual in that a substantial number of the children were raised in families near or below the poverty level. Few twin studies have included children from impoverished backgrounds. What were the new findings? In the author's words: "In impoverished families, 60% of the variance in IQ is accounted for by the shared environment and the contribution of genes is close to zero, whereas in affluent families, the result is almost exactly the reverse."

Female honeybee larvae differentiate into queens or workers with profound morphological differences despite identical genomes. Larvae that will become queens are reared in large vertically oriented brood cells. Queens are fed "royal jelly" by nurse bees, but there is no unique "royal" ingredient (16). What seems to matter are the large differences in the frequency, the amount, and the composition of feedings for queens. Genetically governed programs add their own effects downstream.

To begin with, there are more than 200 primary mutations in beta-globin genes, each with different quantitative effects: most are recessive; a few are dominant.

In the second place, there are modifying genetic loci: those for alpha-globin and for fetal hemoglobin persistence. Comorbid alpha thalassemia can lessen the severity of beta thalassemia by diminishing the alpha chain excess. Thalassemic patients with persistent fetal hemoglobin have milder disease because the gamma chains of hemoglobin F bind the alpha excess.

The genes that control bilirubin, iron, and bone metabolism are tertiary modifiers. The heme products resulting from red cell destruction induce jaundice and gallstone formation; polymorphisms in the promoter gene controlling hepatic glucuronidation of bilirubin can ratchet disease severity up or down. Iron loading compromises cardiac, hepatic, and pancreatic function. HFE polymorphisms influencing intestinal iron absorption modify the severity of heart failure, cirrhosis, and diabetes. The progressive osteoporosis seen in adult thalassemics occurs because iron is toxic to the hypothalamic-pituitary axis. The iron toxicity can be slowed down or hastened by alleles for the vitamin D receptors, estrogen receptors, and collagen.

Fourth, variations in mutant gene frequencies in different populations reflect the evolutionary effects of coselection because of heterozygote advantage against P. falciparum malaria.

Pekka Tienari and his colleagues (26) at the University of Oulu in Finland have reported a long-term follow-up study of Finnish adoptees, half of whom were born to mothers who were schizophrenic. The investigators derived their sample from a Finnish population register that listed all admissions to psychiatric hospitals as well as all adoptions that had taken place over a 20-year time interval. They identified 145 mothers with schizophrenia who had given birth to a child placed for adoption. The adoptee sample was matched demographically with adoptees whose mothers had no history of psychiatric hospitalization. They examined both sets of adoptees and their adopting families on carefully calibrated psychometric instruments when the adoptees had reached a median age of 23 and again when they were 35. The findings provide striking evidence for both hereditary and environmental influences.

Whereas only 8 of the 145 children born to normal mothers had become schizophrenic, 27 of those born to mothers with schizophrenia had. This highly significant difference is clear testimony to a major hereditary contribution. However, assessing the families who had reared the children yielded an equally interesting finding: namely, that 27 of the 32 adoptees who became schizophrenic had grown up in dysfunctional adoptive families.

Caspi and colleagues (27) employed data from the Dunedin Longitudinal Study of Development, which had assessed more than 1000 children biennially from age 3 to 21. Among the factors recorded was exposure to stressful life events, including abuse as a child. When the study subjects were examined at 26, 17% met criteria for a major depressive episode.