Visiting Professor Studies Mechanisms of Cancer

By CAROLINE JASCHKE

Visiting Professor and Postdoctoral Research Fellow Julie Merkle from Princeton University is offering a class this winter term on the potential of stem cell therapy and regenerative medicine. Over the course of four weeks, students in Professor Merkle’s class will explore basic stem cell biology, cell differentiation, gene editing and regenerative medicine. The class will also discuss policies regulating stem cell research and the creative ways scientists have found to circumvent these.

“I hope,” Merkle said in an interview, “that the students come away with an appreciation for the research that has brought us to the point of the exciting advancements we have made in the stem cell world and with an excitement for the potential therapeutics in medicine. I hope they also learn a bit about the bioethics surrounding stem cells.”

Merkle’s own research at Princeton utilizes a specialized type of stem cell, known as germline stem cells, to examine the mechanisms involved in cell division because of the implications defects in this division can have for human diseases such as cancer. Cancer, for example, is caused by the continued, unregulated division of cells. Merkle, therefore, examines the genetic mutations that produce defects in this division process to better understand what can go wrong.

Germline stem cells produce gametes, which are the reproductive cells known as eggs and sperm. In order for the germline stem cells to produce gametes, they must undergo a process of cell division known as meiosis. During meiosis, the chromosomes exchange genetic material through a process called crossing-over. This creates genetic diversity. Essentially, two chromosomes pair-up and then each chromosome breaks off a small section and swaps that section with the other chromosome, so that each chromosome ends up with a small portion of the other chromosome’s DNA.

Because it induces and repairs double-strand breaks in the chromosomes, the crossing-over process involves many of the DNA damage and repair proteins that are needed in all cells of an organism to repair mistakes, called mutations.

“These proteins are a typical part of cell division, including mitosis, and act as checkpoints that prevent ‘genetic instability,’” Merkle said.

Mitosis, like meiosis, is a process of cell division used to create new cells. If properly working, the checkpoints Merkle speaks of should either tell the cell to stop dividing and repair the DNA damage or should recognize a problem and instruct the cell to die. Failure of these checkpoints leads to “genetic instability,” which is the continuation of cell division that causes cancer.

“By learning more about DNA double-strand break formation and repair,” Merkle said, “hopefully that will shed some light on the mechanisms causing cancer.”

She examines these questions by specifically looking at cell division for the production of reproductive cells in Drosophila melanogaster, the common fruit fly.

“The fruit fly makes a good model organism because 75% of the disease-causing genes found in humans are conserved in flies and most of the time these genes are involved in the same cell processes in flies as in humans,” Merkle said. What’s more, flies are cheap, have a short life cycle and their genetics are somewhat simple.

In lab, Merkle induces mutations in female flies to create sterile female flies that are unable to produce eggs. Since making an egg involves cell division, or meiosis, one of the defects produced by mutation may affect this process. After inducing these mutations, Merkle sequences the genome and looks for the mutation within the sequence to determine what gene the mutation is in and whether the gene is also found in other organisms. Merkle studies the mutations of about 20 different genes.

One of the genes Merkle works with has been found to be highly mutated in patients with colorectal cancer. Eventually, after performing many different experiments, Merkle and her lab found that the gene is involved in repairing DNA double-strand breaks. Mutation in this gene causes defective repair of DNA, which triggers the checkpoint to recognize a problem and tell the cell to die. Therefore, no egg is produced and the fly is sterile. Cancer, however, is caused when this checkpoint fails to recognize the problem and the cell continues to divide.

“It’s very exciting to find a gene that is linked to humans and to realize you’re able to discover something no one else has studied,” Merkle said. By identifying this gene and its function, researchers may be able to address cancer-causing defects.

“I really hope the information we gain by studying flies could help diagnose and treat patients with colorectal cancer,” she added. “In the future, I hope to take what we learn about in flies and apply it to research in human cell lines.”

For the month of January, students in Merkle’s class will benefit from Merkle’s experience in the stem cell field through discussions on stem cells and their therapeutic potential.

“Julie is teaching us basic science research skills like reading a paper, while also helping us use critical analysis to discuss the papers,” Samantha Gaines ’18 said. “This could be helpful in later jobs and future classes.”

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Visiting Professor Studies Mechanisms of Cancer