MSU biologist's cell research may help fight cancer, aging process

Contact: Phil Hearn

A Mississippi State biologist hopes his scientific study of how damaged human cells repair themselves may one day lead to improved treatments in the fight against cancer.

Justin Courcelle believes a better understanding of how the body's cellular replication machinery recognizes and restores DNA damage at the genetic level could lead to cancer defense through strategies enhancing the repair process, replacing defective repair genes or killing malignant cells by disabling their repair mechanisms.

"We're trying to better understand how DNA is copied accurately," said the MSU assistant professor of biological sciences. "It seems a little abstract, but it's interesting because it does seem to translate into therapies.… Research in this field has led to the ability to diagnose cancer or identify people who may be predisposed to develop cancer because of the lack of certain repair genes.

"It also has led to the development of new chemotherapeutics to treat cancer, and revealed a possible connection between the genes that control cancer and those that control aging in humans," he added. "Some people who are predisposed to cancer and are sensitive to cell damage seem to age much faster than other people."

Don Downer, professor and head of biological sciences at MSU, said Courcelle "has distinguished himself as an internationally recognized leader in research into DNA repair mechanisms. He is a very enthusiastic scholar who will be a leader in cancer research for many years."

Cancer results from genetic changes in a cell that enable it to grow and divide abnormally, Courcelle explained, noting virtually all genetic changes result from injuries to the DNA template. Those injuries can be caused by a wide variety of agents--including ultraviolet light from the sun, naturally produced toxins in food plants, cigarette smoke, oxygen in the air and even mistakes in duplication of the DNA itself.

Since all cells contain mechanisms that can repair DNA, they usually offset the thousands of injuries occurring each day by faithfully reproducing their genetic material with no adverse effect. If the damage is not repaired, however, Courcelle said, the genetic material may be copied inaccurately--a development believed to cause most cancers.

"Just the fact that you're breathing damages your DNA," said the professor, who is among 18 researchers in MSU's Life Sciences and Biotechnology Institute. "DNA is changing all the time. So if you try to copy that information when it's damaged, it isn't intact anymore and there's a good chance you're going to copy it wrong."

Since bacterial cells duplicate their genetic material the same way human cells do, Courcelle uses E. coli bacteria to determine how the repair processes work and which genes are involved. He knocks out specific genes in the E. coli and then damages the bacteria using ultraviolet light to see if those genes are involved in DNA repair. If the bacterium dies on exposure to UV light after a particular gene is deactivated, that gene is most likely involved in the repair process.

He noted most forms of cancer do not appear until very late in life.

"Your repair systems in the body are so good, they can do it for 50 years without letting too many changes in the genetic information accumulate," said Courcelle, a Rutland, Vt., native who earned a doctorate in cancer biology at Stanford University and completed post-doctoral work at the University of Paris. "Instead of trying to cure all of the different cancers, we need to understand how these repair processes really work and what enhances them."

The professor said one way to help the cell's repair systems is to reduce the level of DNA damage. He noted vitamins C and E, and folate or folic acid, which are forms of a water-soluble B vitamin, are believed to reduce cell damage from carcinogens by "sopping up the toxic agents."

"If we could improve the efficiency of the repair process by just a factor of two, then instead of getting prostate cancer when you're 50, you'd get it when you're 100-- providing you don't die from something else instead," said Courcelle, who came to MSU in 2000.

The Courcelle research team--which includes three graduate students and one post-doctoral student--uses microarrays to determine which genes are "turned off" and which are "turned on" in response to cellular injuries. The technology involves chips that contain all the genes in the E. coli genome, allowing scientists to look at a very large number of genes all at once in a cell.

"The problem with cancer cells is that genes that are supposed to be turned off are turned on because somehow the information got changed, and they're growing when they're not supposed to be," said Courcelle, pointing out one human cell will contain a range of from 25,000 to 100,000 genes.

Courcelle--who first got involved in cancer research as an undergraduate at the University of Vermont to avoid a summer job "flipping burgers"--also shed some light on why people never get heart cancer.

While cells in the skin, colon, liver, prostate, breast, lungs and other vital areas are constantly dividing and replicating their genetic material with varying frequency, he said a person's heart cells never replicate after birth, even though DNA in heart cells sustains damage just as it does in other cells of the body.

"This is why heart attacks aren't so good," he reasoned. "When you kill a certain portion of your heart, you can't regenerate it.

"But although the book is a little tattered, and some of the words or pages may be missing, you never have to copy that out. You never have to copy that information into a new cell, so you're never going to have an opportunity to change that information."

"We think that's kind of a key to cancer," he said. "It's not necessarily the fact that cells are getting damaged. It's when a cell is trying to replicate that damaged template that the information changes. That's what we're trying to study."