Departmental News They Turned Messy Data Into Beautiful Pictures
January 13th, 2008
By Monte Basgall
Proteins are huge, complex molecules that run the cellular machinery of life and knowing their shapes can often provide important clues about how proteins interact with other parts of the cell. But determining those shapes as a way to understand nature and combat disease is dauntingly complex.
Because proteins are smaller than a wavelength of visible light, “taking their picture” has typically required a technique called X-ray crystallography to produce a pattern pinpointing individual atoms’ locations. Unfortunately, the resulting jumble of complex data defies easy interpretation.
The Richardsons turned the jumble into a picture, playing a pioneering role in providing protein structure with a sense of substance and design. They helped translate crystallography data into something intuitive, even beautiful.
“I don’t see how you could possibly describe a protein structure in a thousand words,” Jane Richardson says. “But you can come a lot closer with one picture.”
A seminal 1981 survey in the review journal Advances in Protein Chemistry first showed the scientific world what became known as “ribbon drawings” or “Richardson diagrams.” They were Jane Richardson’s hand-drawn interpretations of the structures that she, her husband and others had derived by bouncing X-rays off the atoms of crystallized proteins.
Today, much like standardized highway signs, the visual language of protein structure that the Richardsons invented is the standard in their field, although hand-made drawings have largely been replaced by computer graphics. Hardly a week goes by that a ribbon drawing isn’t featured on the cover of at least one scientific journal.
“As Louis Sullivan, the famous architect, said, ‘form always follows function,’” says Peter Agre, Duke professor of cell biology who shared the 2003 Nobel Prize in chemistry for determining the shape of a protein complex that lets water in and out of a cell. “Jane and David’s work allowed us to reveal the form of proteins, and from there it was easier to understand their function.”
The diagrams Agre and others use still follow Jane Richardson’s formula. Corkscrew structures called alpha helices are shown as coiled ribbons. Molecular loops are depicted as round ropes. Extended protein segments, called beta strands, become ribboned arrows that twist together and gather visually into beta sheets.
Jane Richardson slightly exaggerated perspective in her drawings to accentuate their three-dimensional quality.
“I’m not good at drawing things in general,” she says. “That’s why it took me two whole years to work out how to do these things!”
Sitting in the Nanaline H. Duke building offices that they share with examples of their protein models — one incorporated into a stained glass window — the two biochemistry professors recalled how their collaboration on protein structure began at MIT, before they arrived at Duke in 1970.
In the early 1960s David was working on a Ph.D. at MIT. Jane, an amateur astronomer and science award winner in high school, had finished a master’s degree in philosophy at Harvard and tried teaching high school, but grew fascinated by her husband’s work on protein structures and signed on as a lab technician to read out the raw X-ray data. After seven years of work they produced a 3-D image of all the atoms in a protein structure.
“We would look at the protein’s backbone trace and try to draw on the blackboard what we called its ’signature,’” David recalled. “Jane developed from that what was later regularized into ribbon drawings. She wasn’t the first to do ribbons, but she was the first to develop the rhetoric to make them into a language. I was there more or less for technical support,” he added modestly.
“You were the one who was the expert at making the equipment work,” she replied. “And I looked at the data quality.”
In 1985, her ribbon schematics won Jane Richardson a prestigious MacArthur Fellowship. By then, the Richardson laboratory was a fixture at Duke, and the couple had diversified beyond interpreting protein structures to designing novel new kinds of proteins.
In 2006, Jane Richardson was also elected to the National Academies’ Institute of Medicine, a special feat for someone who never received an M.D. or Ph.D.
Produced by: Monte Basgall senior science writer, Duke News and Communications.
NEW PATHWAY PROVIDES MORE CLUES ABOUT BRCA1 ROLE IN BREAST CANCER
DURHAM, N.C. —A breast cancer gene’s newly discovered role in repairing damaged DNA may help explain why women who inherit a mutated copy of the gene are at increased risk for developing both breast and ovarian cancer.
The discovery also could lead to more effective therapies for women with and without mutated copies of the BRCA1 gene, according to a study led by Duke University Medical Center researchers.
“Since it was discovered in 1994, BRCA1 and its role in preventing and causing cancer has been intensely studied, and our research represents an important piece of the puzzle,” said Craig Bennett, Ph.D., a researcher in Duke’s Department of Surgery and lead investigator on this study. “This study has identified an important mechanism by which BRCA1 comes into play when DNA the basis for all cell function is damaged. We have shown that this theory holds up not just in scientific models but in human breast cancer cells as well.”
The findings appear in the January 16, 2008 online edition of the journal PLoS ONE. The study was funded by the United States Department of Defense, the National Institutes of Health and the Italian Association for Research on Cancer.
The researchers first looked at yeast to demonstrate that a molecular pathway that is particularly susceptible to BRCA1 influence is also crucial to normal cell function.
“The BRCA1 pathway we discovered is directly involved with the critical process of transcription, in which RNA acts as a messenger between DNA and the making of proteins,” Bennett said.
DNA damage is a normal result of exposure to environmental agents, such as carcinogens, and the response to this damage can be influenced by other normal human processes such as aging and hormonal changes, Bennett said. It’s what happens to RNA transcription after damage occurs in DNA that is BRCA1-dependent.
“We found that BRCA1 acts together with transcription to detect DNA damage and to signal the cell to repair itself,” Bennett said. “When BRCA1 does not function correctly, as when it is mutated, DNA damage remains un-repaired and cancer can occur.”
The researchers applied their findings in yeast to human breast cancer cells, with the same results.
“The fact that we were able to duplicate our results in human breast cancer cells is hugely important,” said Bennett. “Yeast is a wonderful model organism that has been used to make significant discoveries in many areas of science and medicine, including Parkinson’s and Alzheimer’s diseases, but the ability to replicate results in human cells is key.”
Bennett said the discovery will lay the groundwork for further investigation of the role of BRCA1 and possibly lead to new therapeutic strategies targeting the genes or protein products within this pathway.
Women who have inherited a BRCA1 mutation have up to an 80 percent risk of developing breast cancer in their lifetime, and they are also at risk for developing the disease at much younger ages than women without the mutation, according to the American Cancer Society. Their risk for developing ovarian cancer is about 40 to 50 percent, compared to just over one percent for the general population. The mutation is most often found in women with Eastern European Jewish origin, but can be found in women of any race.
“Someday we hope that this research will lead to the development of more effective ways to treat both the women who have inherited a mutated copy of the BRCA1 gene and those who have not,” Bennett said.
Other researchers involved in this study include Tammy Westmoreland, Carmel Verrier, Carrie Blanchette, Tiffany Sabin, Hemali Phatnani, Yuliya Mishina, Gudrun Huper, Alice Selim, Ernest Madison, Dominique Bailey, Adebola Falae, John Olson, Arno Greenleaf and Jeffrey Marks of Duke; and Alvaro Galli of the Institute of Clinical Physiology in Pisa, Italy.