Each dot represents one nucleotide. Black dots are the nucleotides most likely to arrange themselves in base pairs, creating the hairpin formations that separate sections of the code from the rest of the genome.
At first, Weeks was more interested in solving the puzzle of how RNA genomes are put together. Soon he realized he could apply the findings to a problem that would really matter.
Scientists have sequenced the genetic code of HIV-1 many times, but this map is their first complete look at the genome’s intricate structure.
Kevin Weeks with the team that helped him decode HIV (left to right): Ron Swanstrom, Joe Watts, Weeks, and Christina Burch.
Why would a chemist take on the world’s toughest virus?
In Kevin Weeks’ lab, a section of wall is covered with results from his early HIV experiments. The printouts look like electrocardiogram readings gone wrong: a series of spikes and dips without rhythm or pattern.
From these figures, Weeks, professor of chemistry at UNC, and his lab created the first-ever model of an entire HIV-1 genome, a discovery that has widespread implications for understanding how viruses like HIV infect humans.
Several years ago, this group developed techniques to map the structure of ribonucleic acid (RNA) down to the level of nucleotides, the smallest pieces of a viral genome. Weeks’ main interest, as a chemist, was in solving the puzzle of how RNA genomes are put together, but he wanted to apply it to a problem that would really matter.
The HIV genome – or any long piece of RNA – is particularly difficult to map. Unlike DNA, with its more familiar double-stranded helix and twisting ladder of orderly base pairs of nucleotides, RNA usually has a single strand. These strands form pairs, but don’t link nucleotide by nucleotide like DNA. Instead, each individual RNA strand folds to create tiny structures of its own, little double helices and loops scattering throughout a genome.
What to do with this structured jumble of genetic code? Weeks’ lab measured the nucleotide flexibility: how likely were nucleotides to form single-stranded loops and curves versus remaining more rigid, less flexible?
Each nucleotide of a piece of RNA was treated with an organic compound. If a nucleotide forms chemical bonds that hold it in a rigid formation, it doesn’t react much with the compound. If there are fewer chemical bonds, a nucleotide reacts more strongly, showing that it’s free to form single-stranded loops and curves. The scribbles on Weeks’ wall are measurements of how the nucleotides reacted.
Weeks and Joe Watts, a postdoctoral researcher, ran a computer program that translates the reactivity data into complete pictures. The genome was full of loops, double helices, and other structures that no one had ever identified before.
“I was shocked that we found so much structure,” Watts says.
So what do these never-before-seen structures actually do? Researchers will spend years answering that question, Weeks says. But his findings are already having a big impact on HIV research. There is emerging work from many labs – at UNC and worldwide – where the genome structure explains many previously poorly understood features of HIV. Weeks’ original hypothesis, that there is much to be learned about HIV and other viruses from analyzing intact RNA genomes, is panning out.
Weeks’ lab is still working on its structure-modeling technology. He wants to decode the HIV-1 genome structure at different stages to make a movie of how it looks over a complete replication cycle. This will take who-knows-how-many virus particles and whole-genome snapshots to complete.
“But in my head,” Weeks says, “I’ve got that next five-year plan.”
Kevin Weeks is a professor of chemistry in the College of Arts and Sciences. Joseph Watts finished his postdoctoral work in December 2008 and is now a research scientist at Syngenta Biotechnology. The study was the cover story of the August 6, 2009, issue of Nature. Other UNC authors were Ron Swanstrom, director of Carolina’s Center for AIDS Research; Christina Burch, an associate professor of biology in the College of Arts and Sciences; Kristen Dang, then a graduate student in biomedical engineering; and Christopher Leonard, a research specialist in the department of chemistry.