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hat if a molecular sentinel located in your body could detect early-stage cancer and then deliver drugs quickly to kill the malignant cells? It may sound like science fiction, but Columbia Health Sciences researchers are actually working to develop such a novel method for disease detection and treatment. The device would be applicable to astronauts in deep space and could revolutionize the fight against cancer on Earth.

In January, NASA and the National Cancer Institute awarded a $1.5 million, three-year grant to a group of P&S researchers to develop a revolutionary diagnostic and therapeutic methodology based on DNA’s ability to form autocatalytic complexes with proteins. NASA is interested in supporting novel technologies to treat astronauts on long space flights with no doctor on board. NCI would like to detect and treat cancer at its earliest stages in deep tissues, something that is impossible with current technologies.

“This is the first time NASA and NCI have requested such far-sighted proposals,” says Dr. Donald Landry, associate professor of medicine and principal investigator on the project. “They want us to develop a system that’s never been done before. We have developed all the necessary components but the challenge will be stringing them together.” The grant process was very competitive. Seven research groups received grants; 53 applied for funding.

To fulfill the grant, Dr. Landry, who is also director of the division of clinical pharmacology and experimental therapeutics, and Dr. Milan Stojanovic, associate research scientist and a co-investigator on the project, will first devise a diagnostic tool that will use DNA attached to a small chemiluminescent reporter molecule. Once the diagnostic is developed, they plan to create a therapeutic version. This group is also developing molecular zip codes to ensure that this tool will find its way to its specific deep tissue “address.”

How will the diagnostic work? If the DNA recognizes a tumor protein in the deep tissue, it will change conformation and in an autocatalytic process cleave the indicator molecule into the blood stream. When the indicator reaches the urine, it will be identified by a light emission from the released reporter molecule.

Once the diagnostic is sufficiently developed, the investigators plan to use the method to deliver medications. “Sensors will make decisions about whether the cell is cancerous and whether the drug should be delivered,” Dr. Stojanovic says. “For example, the presence or absence of one or more specific proteins in a cancer cell will trigger the delivery.”

The government gave the researchers the grant based on their development of molecular-scale sensors. The sensors evolved from Dr. Landry’s efforts to create catalytic antibodies to treat cocaine addiction, an invention that he and Columbia University have patented. After joining Dr. Landry’s group four years ago as an NIH-funded postdoctoral research fellow, Dr. Stojanovic developed several DNA-based cocaine sensor systems in the group’s search for new molecular interceptors for cocaine. Dr. Stojanovic recently was appointed assistant professor of medicine and is setting up his own laboratory.

Dr. Stojanovic’s independent research involves molecular-scale computation systems, among other projects. He has constructed a set of logic gates, the building blocks of a digital circuit, using nucleic acid catalysts. He is now connecting these gates into circuits that will be able to make “decisions,” a useful characteristic for the NASA and NCI tumor identification and treatment research. A paper is coming out shortly in the Journal of the American Chemical Society.

As part of the NASA and NCI grant, Dr. Stojanovic has hired Dr. Dragan Nikic, a postdoctoral research scientist; Tiffany Mitchell, a master’s student in biotechnology; and another postdoctoral scientist, who will join the group in April. Dr. Nikic is engineering the DNA-detection system to recognize thrombin (a component of blood clot formation) and then release adenosine as a model small molecule. Thrombin was chosen as a model system because its interactions with DNA are well characterized and because of its therapeutic importance. The next stage will be to have thrombin release luciferin, a light-emitting molecule. Ms. Mitchell is working on the tissue zip codes.

Dr. Stojanovic is cautiously optimistic about whether the method will actually treat disease. “The space-oriented research we are doing is really a fundamental quest for knowledge that could one day lead to more sophisticated treatments,” Dr. Stojanovic says. “We must break the futuristic vision into elementary steps. We need to understand and then demonstrate each of these steps. This process will take some time.”



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