The Nobel Prize brought Khorana fame, but it also brought even higher expectations. Though he may not have minded the fanfare, psychologically, all the attention took its toll. A short time after returning to Madison from Stockholm, he suddenly disappeared from his laboratory apparently in a state of mental exhaustion, possibly depression. For several months he was unavailable. Laboratory members tracked him to Vancouver, where he was recuperating, but showed little interest in an immediate return. Friends said that he sat by the water for hours every day staring into the distance. But, soon, a crisis emerged within the laboratory as a dispute burst open between two factions that refused to work together. RajBhandary duly reported the problem to Khorana and it finally had the effect of making him return to establish peace. The laboratory could start functioning again.

Laboratory members also recall that wherever Khorana went—and he gave many seminars in the late 1960s—he was repeatedly asked whether he had finished synthesizing a gene. Was it done yet? When would it be done? He must have felt immense pressure though, after that initial retreat to Vancouver, it would not manifest itself publicly.

He had brought the pressure on himself. In the early 1960s, when not even the sequence of a single gene was known, he had announced his goal of the total synthesis of a functional gene. He was always explicit that the drive to decipher the genetic code was a mere detour from that pursuit even though it had brought him fame and a share of a Nobel Prize. Synthesizing the gene was a much more challenging—and, therefore, intellectually satisfying—problem: