Hanging in Jeff Kieft's laboratory at the University of Colorado Denver is a sign that reads "Hope is not a method." Posted by his students, the statement—a favorite of his former battalion commander's—is a carryover from Kieft's days as a U.S. Army officer.
"The bottom line was that perseverance and attention to detail matter. Those are two things that have carried over to my research," says Kieft, whose dexterity in determining the atomic specifications of molecular structures—the hallmark skill of the structural biologist—is as essential to his research as was calculating the right amount of ordnance for a phalanx of tanks.
Kieft is exploring the structure and function of viral RNAs, genetic material that helps direct the synthesis of proteins involved in infection and pathogenesis. "I'm interested in how the structure of certain viral RNAs enables them to hijack the basic biological machinery of the cell," Kieft explains. His ultimate goal: to find targets for drugs that thwart infection by disabling or blocking RNA.
Viruses are genetic paupers. Many of the most medically important viruses, including pathogens such as hepatitis C and HIV, have only a handful of genes of their own. They depend on host cells to provide them with the biological machinery to complete their life cycles. "Viruses tend to be more genetically compact, thus they have to do more with less," says Kieft, noting that the microbes use RNA to manipulate their hosts in myriad ways.
Kieft has used the hepatitis C and HIV-1 viruses and several others as model systems. Some of these viruses use RNA to take a clever shortcut that bypasses some steps in the protein-making process the viruses use to make more viruses. These viruses and other pathogenic viruses such as polio depend on internal ribosome entry site (IRES) RNAs—responsible for making the proteins a virus needs to survive and make copies of itself—to successfully infect cells. Using x-ray crystallography, a technique that lets scientists map the arrangement of atoms in a crystal of DNA, RNA, or protein, Kieft's lab determined the complete structure of a viral IRES RNA.
Hitching the three-dimensional pictures of the RNA to biochemical and functional studies of the molecule, Kieft has revealed how the RNA folds and attaches to the ribosome, a specialized structure in the host cell that produces proteins. When co-opted by the virus and its IRES RNA, the cell ribosome turns its protein-making abilities to the service of the virus, which needs the proteins to build new viruses. Insight into such molecular detail is an important step toward developing a customized drug to target the RNA, disable it, and short-circuit the cycle of infection.
Although he majored in chemistry at the U.S. Military Academy at West Point, Kieft developed an interest in the molecular structures of biology while serving in the Army in Germany. The story of the discovery of the structure of DNA by James Watson and Francis Crick has exerted an enduring influence: "It was the elegance of nucleic acid structures that interested me," says Kieft, referring to the artful three-dimensional structures of genetic molecules. "I started studying RNA structure in graduate school, and I've never left it. It is a fun time to be in this field. We keep discovering more and more."
After his Army service, Kieft trained at the University of California, Berkeley. Between his postdoctoral fellowship at Yale and beginning his current faculty position, he spent a year as a fellow in the White House Office of Science and Technology Policy. "I have an interest in knowing about and participating in public policy. My year in the White House science office was interesting. I never knew what was going to land on my desk," says Kieft, recalling experiences as diverse as helping to develop policy on excess agricultural runoff polluting the Gulf of Mexico, probing security issues associated with shipping containers, and serving as a liaison during the cleanup of the Hart Senate Office Building after its contamination with anthrax spores.
Kieft is now helping to direct a new program on science policy at the University of Colorado Denver, where he hopes to help students gain insight into how the worlds of science and policy making intersect. This interest meshes with his efforts to help the public understand how evolutionary theory need not conflict with faith-based views of life, a topic he often speaks about to church groups. Kieft considers teaching and science education as critically important. He especially values time with his students. "I want my students to have the same opportunities I had" to be in the lab and work with other scientists. "On any given day, we might find something brand new."