Nathans continued to elucidate the structure and functions of SV40 during the early 1980s, and became particularly interested in the effect of proteins such as large T-antigen on the sequence of DNA replication and gene expression in the virus. The T-antigen protein is one of the first synthesized after the virus infects a cell. Nathans' work helped establish that T-antigen then initiates the replication of the SV40 DNA by binding to the replication start point on the DNA. Suspecting that analogous processes occurred in mammalian cells, he began to investigate the operation of cultured mouse cells as they entered the growth cycle. Growth in mammalian cells is regulated by a variety of protein growth factors, which trigger a series of biochemical events inside the cell, leading to the sequential expression of specific genes. Nathans' studies found that some of the genes activated early in this process regulate the expression of other genes needed to initiate DNA replication, and he went on to isolate and characterize many of these "immediate- early" genes. His subsequent studies looked more closely at the ways in which various growth factors stimulated activities within the cells.

Throughout this period, Nathans had administrative and advisory responsibilities in addition to his research, teaching, and mentoring. He headed the department of Microbiology (which became the department of Molecular Biology and Genetics in 1981) from 1972 to 1982. In 1982 he was named a Senior Investigator of the Howard Hughes Medical Institute (HHMI). HHMI is an unusual medical research organization established in 1953 to directly support investigation in genetics, immunology, and other areas. Investigators are given renewable appointments for 3, 5, or 7 years, depending on academic rank, and become HHMI employees, deriving their entire salaries and research budgets from HHMI. They are expected to spend at least 75 percent of their time on research. At the same time, investigators must remain as faculty members in their own institutions, and the host institution establishes a formal collaboration agreement with HHMI to cover arrangements for office and lab space. As a Senior Investigator, Nathans was responsible for executing the details of this collaborative arrangement.

Nathans had long been recognized by his scientific colleagues as a gifted administrator as well as a brilliant researcher. In 1995, these talents were further acknowledged when he was asked to serve as interim president of Johns Hopkins University. Though the post was only for a year, Nathans was determined not to be just a place-holder. Instead, he worked to expand undergraduate education by opening a center for the performing arts, and he actively guided the Johns Hopkins Medical Institutions through a transition faced by many university medical centers during the 1990s: redefining the financial and administrative relationship between medical school and hospital system to fend off advances from for- profit health care corporations. Nathans enjoyed the challenges of this year, comparing it to his medical internship, where he was forced to make quick decisions based on limited information.

After his term as JHU president, Nathans looked forward to resuming his teaching and research, continuing what he always regarded as a "privileged life." He carried on with these activities after he was diagnosed with leukemia in 1997, but succumbed to the illness on November 16, 1999.

In his memoir of Nathans for the National Academy of Sciences, one of his former graduate students, Daniel DiMaio, noted, "Dan Nathans changed the way we viewed viruses and genes. When he began his studies dissecting the genome of SV40 in 1970, genes were terra incognita. The coastline had been roughly charted by classical genetic experiments, but the vast unbroken interior stretched on toward a distant horizon. Dan taught us how to draw lines of longitude and latitude on this map, and gave us the first lessons on how to fill in all the glorious detail. The true measure of this work is that today we can barely imagine how to analyze viruses and genes without using the approaches pioneered in Dan's laboratory. Challenge a student to design a molecular genetics experiment that doesn't entail the use of restriction enzymes or molecular cloning. You might as well ask for bricks without straw."

However, DiMaio continued, "Despite the enormous importance of his scientific contributions and administrative service, those who knew Dan will remember him chiefly for his personal qualities. He was gentle, soft-spoken, modest, scrupulously fair, and unswervingly honest. His success was leavened by his humility and his intelligence by his wisdom. . . [C]onversations about Dan focused not on his scientific accomplishments but on these extraordinary human characteristics. To work closely with Dan Nathans was a privilege beyond measure, an experience that forever shaped our science and our lives."