Stephen Goff distinctly remembers the impact a 1972 article in the scientific literature had on him as an undergraduate. It was the seminal paper by Paul Berg at Stanford describing the procedure for creating one of the first recombinant DNAs. He had made the molecule by cutting open two circular DNAs with enzymes, adding DNA "tails" to their ends with another enzyme, and finally sealing up the joints with ligase, to re-form a larger circle.
"As a student, I was a computer programmer and after reading the paper I told my friend that biology had just become programmable," Goff says. "You could now make DNA do whatever you wanted and control its actions from then on." The advance by Berg, who shared the Nobel Prize in Chemistry in 1980, and others ushered in the recombinant DNA era, in which scientists in academia and industry manipulate DNA and other nucleic acids for analysis and use as reagents and drugs.
Goff would also contribute to molecular biology's emerging revolution. In 1973, he became a graduate student in Berg's laboratory and developed the first methods to put recombinant DNA molecules, using the animal SV40 virus, into mammalian cells. The hybrid molecules replicated inside the cells, which properly read the foreign genetic material. "It was a very exciting time," Goff says. In the 1950s and 1960s, researchers knew a bit about how genes work, he explains. "But after the 1970s, you could direct the genetic program and control the story. And I have been learning more about how to control the cell's program ever since."
Today, Goff's research focuses on the retrovirus, which he started studying during his postdoctoral fellowship in the Massachusetts Institute of Technology laboratory of David Baltimore. Baltimore shared the Nobel Prize in Physiology or Medicine in 1975 for his work on reverse transcriptase, the enzyme that makes DNA from RNA, the genetic material of retroviruses. After a retrovirus infects a cell, retroviral reverse transcriptase turns the RNA into DNA, which integrates into the DNA of the cell. Ultimately, the incorporated viral genetic information directs the cell to make new viral particles to infect other cells.
Goff became interested in retroviruses, he says, because of the opportunity to understand the genetic machinery the virus uses to enter the cell, integrate its DNA into the chromosome, and reawaken later—even generations later—to reproduce. "Exploiting the cell's own machinery in this way—it would be hard to think of a more clever, or perhaps diabolical, system," Goff says.
At the time he started in Baltimore's laboratory, little was known about the steps the retrovirus uses to integrate and reproduce inside cells. Initially, Goff worked on a retrovirus that caused leukemia in mice as a model system, but in the 1980s he began to also work on HIV, the retrovirus that causes AIDS. In his career, Goff has characterized many of the genes and protein products retroviruses use to live inside animal and human cells and to cause disease.
Goff is particularly proud of his identification in1980 of the abl oncogene from the Abelson virus and, later, of its counterpart in the normal DNA of a mouse chromosome. Abl was one of the first oncogenes discovered. An oncogene is a gene that causes a healthy cell to become a cancerous cell. Abl codes for a tyrosine kinase, which later research showed is overexpressed in chronic myelogenous leukemia in humans and is the target for the anticancer drug Gleevec, an inhibitor of the ABL protein. "We cloned the gene from the mouse virus that was the cause of the viral cancer," Goff says. "People later discovered that it was the same gene that was altered in human tumors."
Goff continues to study the transforming properties of the abl gene and how its gene product contributes to the cancerous condition of a cell. He also has developed a mouse lacking abl to understand the role of the gene's protein product in normal physiology.
Currently, most of the activity in Goff's laboratory is identifying the cellular factors that retroviruses, including the mouse leukemia virus and HIV, use to live and replicate inside their hosts. "Understanding viral–host interactions is important to fill out the picture of the viral life cycle, and characterizing the relationships also might lead to new ways to prevent retroviral infection," Goff says. He is interested in host proteins that the viruses need and exploit and also in those that work to inhibit virus. For example, Goff has found a novel cellular protein, called ZAP, that robustly blocks infection by many viruses.
Goff credits his success as a researcher to great teachers and mentors who inspired him when he was starting out and to wonderful students and postdocs for their energy and creativity during his time as a laboratory director at Columbia for more than two decades. He attributes his first interest in science to his older brother, also a molecular biologist, and his father, who was a contractor, boat builder, and antique clock restorer.
"When I was growing up we always had dozens of broken clocks and their parts all over the house that we were in the course of fixing," Goff says. "In some ways, I think of the world as a functioning collection of little parts. Of course, now the parts I am interested in are molecules, but they work in similar ways to those clock parts."