Turning necessity into success
Residential Physician Jesse Salk pipets DNA solution into a thermal cycler. The thermal cycler heats the DNA solution to allow the first step of the polymerase chain reaction process.
Residential Physician Jesse Salk pipets DNA solution into a thermal cycler. The thermal cycler heats the DNA solution to allow the first step of the polymerase chain reaction process.Photo by Joshua Bessex
Inspiration can hit anytime, and for one group of UW scientists, it happened to hit during an ice-climbing trip in the Canadian mountains.
En route to this adventure, Jesse Salk and Michael Schmitt were at the airport, thinking of how they could more accurately sequence DNA. This led to the research team developing a new method of DNA sequencing — called error corrective sequencing — in order to learn more about a variety of diseases in their ongoing research project. A paper about this new sequencing technique was published last fall and research still continues on the topic.
“I think one of the things that I admire about this project is that we came up with this idea when we weren’t sitting behind a computer,” Salk said. “[Schmitt and I] were out doing something we both really like doing, and I’ve always felt that some of the best ideas come when you are doing things you enjoy — you can’t really force creativity.”
Normally in DNA sequencing, the DNA strand is tagged and then sequenced. Instead of using only one side of the DNA strand, which is the current method, this new technique — thought up by Salk and Schmitt and refined by the research team — tags both sides of the strand, and then compares the errors from one side to those on the other side. Mutations occur in the same spot on both sides of the strand, but are often mistaken for errors. These mutations can help scientists in a multitude of ways.
The theory behind this project came from Lawrence Loeb, UW professor and director of the Gottstein Memorial Laboratories. In 1974 he hypothesized that when DNA malfunctions, it accumulates random mutations at a much quicker rate in malignant cells versus normal cells.
“If you have these enormous frequencies in mutations in the cancer, it means that by the time you have a tumor there will be cells in your tumor that will be resistant to anything you ever thought of, [which] limits the ability to treat cancer,” Loeb said.
The group hopes that advances in DNA sequencing can help provide doctors with a better way to diagnose and treat various forms of cancer. By being able to sequence the cancer in a way that reveals mutations, not just errors, doctors can verify what mutations are present and which treatments can effectively battle those mutations and malignancies.
To make the sequencing possible, the team used an existing sequencing machine and wrote new programming code for the machine to use. When scanning billions of nucleotides, having tens of thousands of errors is not efficient. Scott Kennedy, post-doctoral fellow in pathology and co-author of the research paper, attributes some of the errors to damage in the DNA from sequencing. When sequencing both strands, identifying markers can correlate errors to mutations.
“We got really good results on the first try,” Kennedy said. “That almost never happens in science.”
The next steps will be applying these techniques to specific parts of the body. The researchers are currently applying these sequencing techniques to chemotherapy-resistant mutations in cancerous tumors and mutation phenotypes that Loeb hypothesized in the ’70s, as well as biomarkers for neurodegenerative diseases.
Kennedy is using the new technique to look at potential benefits in detecting and treating mitochondrial DNA (mtDNA) disorders that impact a cell’s ability to produce energy. Mutations inside mtDNA can be passed down from parents to children or can happen due to adverse effects from drugs, infections, or other causes.
Patient samples are already being used in the lab, so clinical trials may not be too far off — about one or two years away — though it would still be several years before the technique is widely used by doctors.
Loeb would like to know what the differences are in cells from different parts of the body, such as a person’s knee versus their elbow, or why the mutations in cancer cells occur in the first place. He would also like to see this technique used to decide what therapies to avoid giving cancer patients.
It took the team less than a year to go from mountainside idea to working product, but there’s still more research to be done. All parties of the research team agree that any clinical applications from this research are a few years off due to regulations and trial studies, but the future is hopeful.
Reach reporter Deanna Isaacs at firstname.lastname@example.org. Twitter: @DeeLiteraryOne
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