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Loneliness is a main theme of the novel and the best place to start is where the novel does - Soledad. The setting is a significant choice by Steinbeck due to the connotations Soledad has with "solitude" (it is the Spanish translation).
Through the character Slim (who is referred to as "God-like" hence giving him the characteristic of omnisciency) Steinbeck comes to the conclusion that people in the time period (the novel is set during The Great Depression) "never seem to give a damn about nobody." This quote here reflects upon the predatory nature at the time where everyone was looking out for number one, themselves, and therefore leads to loneliness because of a lack of care for others.
Both Crooks and Curley's wife feel loneliness due to segregation to the others. Crooks is segregated from the bunkhouse and therefore lives alone and he has no one to talk to which inevitably leads to his loneliness. Crooks claims that loneliness can be eradicated through talking and the atmosphere of "just bein' with another guy. That's all." Crooks understands this but the colour of his skin is a barrier which prevents him from being with other guys and leading a more friendly life. He finds the concept of friendship delightful and this is shown when his scowl is defeated by "Lennie's disarming smile," the smile being a symbol of friendship. Curley's wife faces her segregation due to being a women and the general view that women should be housewives and no more is shown by Carlson when he tells Curley that his wife should "stay the hell home where she belongs." This segregation combined with Curley's jealousy if he was to catch her talking to another man, prevents her from having any chance of talking.
George and Lennie are special in the regard that they travel together. It's seen as unsual by the others and The Boss disregards the possibility that George would be travelling with Lennie for any other reason than money hence asking him what "stake" he had, implying a financial gain by travelling and being alongside Lennie. This attitude reflects upon the corruption of humans during the set time period because it has gotten to the extent that trust has been lost and it has become the norm to be in solitude.
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