Kenneth D. Karlin, the Ira Remsen Professor of Chemistry in the Krieger School of Arts and Sciences, recently was named a co-recipient of one of the University of Maryland's invention of the year awards.
Karlin received the Life Science Invention of the Year award with collaborator Steve Rokita, a professor of chemistry and biochemistry at the University of Maryland, College Park, and three of their students. The group won the award, one of three given annually by the university, for creating three copper complexes--molecules composed of copper atoms bonded to designed organic structures--and characterizing their reactions with DNA. One of these new compounds is currently being tested as a potential anti-cancer agent at the National Cancer Institute, and the compounds could also have additional, more basic applications in biotechnological research.
Karlin is a specialist in bioinorganic compounds, which are found in life forms but have an inorganic ingredient like a metal. He is particularly interested in their relationship to enzymes that include copper and iron atoms, and the interactions of these enzymes with compounds like molecular oxygen, nitrogen oxides and other compounds found in the environment.
Both iron and copper are trace elements, found only in very small amounts in biological systems. They have to be managed carefully in cells to avoid toxic side effects, according to Karlin. But they're essential for the role they play in enzymes that get crucial chemical jobs done.
"Copper complexes, for example, are used in nature to carry molecular oxygen in the blood of blue-blooded creatures like some crabs, lobsters and spiders," Karlin explains. The iron complex hemoglobin serves the same function in humans.
By combining specific metal atoms and organic structures, nature tailor-makes enzymes for particular purposes. To help determine how the interaction between metals and other enzymatic structures creates those specializations, Karlin's group creates novel molecules. They then characterize the structure and reactivity of the molecules.
Based on previous information in the scientific literature, Karlin wondered if any of the molecules his lab was making could cut DNA. He contacted Rokita, who specializes in the study of the conformation or shape of DNA, and chemical reactions linked to specific DNA sequences.
"We had talked casually for some time about doing a collaboration," Rokita recalls. "And it was really a case of the right student at the right time and place who wanted to extend her work."
That graduate student, then completing her doctorate at Johns Hopkins, was Kristi Humphreys. Now doing postdoctoral work at the University of California at Berkeley, Humphreys had been involved in the initial testing of the three copper compounds in Karlin's laboratory. She took them to Rokita's lab at College Park to study how they interacted with DNA.
"I had previously looked at interactions between nickel complexes and DNA," Rokita says, "so I knew how to start looking at the copper complexes and DNA, and the proximity of our labs made it easy to collaborate."
The new compounds interacted with DNA in specific ways, cleaving DNA at particular positions related to the sequence of bases in the DNA and, in some instances, abnormalities in the structure of the DNA itself.
At the National Cancer Institute, one of the three new copper compounds has shown promise in treating cancer in cell cultures, and it will soon be tested in mice. The compound's therapeutic effects have been compared favorably to those of a widely used chemotherapeutic drug.
Karlin, meanwhile, is eager to get a better understanding of nature's chemical tool-making techniques.
"How is nature making the environment around the metal special to carry out some unique biological function?" he asks. "We'd like to find out how this works and see if we can expand on it to create systems with new specificities." Such insights could be valuable to the pharmaceutical and petrochemical industries, according to Karlin.
Further studies are planned in collaboration with Rokita to test the new compounds' abilities to interact with RNA.
Additional winners on the award were Lei Li, currently a graduate student at Hopkins, and Narasimha Murthy, a former postdoctoral student at Hopkins who is now an assistant professor at IIT Madras in India.