Molecular Biology, Cancer Biology
The University of Texas Southwestern Medical Center
Dr. Mendell is also a professor of molecular biology, a member of the Simmons Cancer Center, and a member of the Center for Regenerative Science and Medicine at the University of Texas Southwestern Medical Center, Dallas.
MicroRNAs and Other Noncoding RNAs in Development and Disease
When Joshua Mendell set up his research lab in 2004, the study of microRNAs was an emerging field. Hundreds of these small bits of RNA had been found in plants and animals, and scientists knew they affected a variety of biological processes by regulating gene activity. Mendell dove in and quickly established himself as a leader in determining how microRNAs influence development and disease.
His first big discovery came in 2005, when he showed that a well-known cancer-promoting protein, MYC, directly stimulates production of a specific cluster of six microRNAs. He and others have since demonstrated that these microRNAs contribute to MYC's ability to drive tumor formation. Work from Mendell's team has revealed involvement of microRNAs in several other critical cancer pathways as well, and recently the lab showed that certain microRNAs are important for wound healing. Mendell's group has also uncovered new mechanisms through which the abundance of microRNAs is controlled in normal tissues and in tumors.
Ultimately, Mendell is interested in developing new therapies for human disease, and his work in animal models has provided persuasive evidence of the therapeutic potential of microRNAs. His team slowed the growth of liver tumors in mice dramatically by giving the animals a specific microRNA that was present at lower levels in cancer cells than in healthy liver cells. The treatment killed tumor cells but preserved healthy cells, suggesting that such therapies might be well tolerated and effective.
Most recently, Mendell's group has applied similar approaches to study the functions of other types of noncoding RNAs, uncovering surprising new roles for these transcripts in normal physiology and in cancer.
On the desk in Joshua Mendell's office is a framed photograph of him working with his soon-to-be wife Kathryn O'Donnell at the Johns Hopkins University School of Medicine. The snapshot records a moment in 2004 when the two discovered that microRNAs play an unexpected role in the biology of cancer cells.
That discovery revealed an important relationship between microRNAs - short pieces of single-stranded RNA that do not encode a protein but control the expression of genes - and a protein called Myc. Myc controls normal cell proliferation and, when altered, causes cancer.
"It was the first demonstration that microRNAs can act as key components of well-known cellular pathways such as the functional program controlled by Myc," Mendell says of the research, published in Nature in 2005. Researchers had not previously known that microRNAs are used by pathways that play a critical role in normal cellular functions and whose activity becomes abnormal in disease states.
Mendell showed that high levels of the Myc protein, a common attribute of cancer cells, result in activation of a specific group of microRNAs. These microRNAs, in turn, can drive cellular proliferation and prevent cell death, thereby contributing to tumor formation. He has since shown that excessive amounts of the Myc protein also lead to repression of a large set of microRNAs whose activity normally slows tumorigenesis.
Today, Mendell uses mouse and human cells to discover how microRNAs are regulated and how they affect other aspects of cell signaling. He has been building evidence that many microRNAs act either as oncogenes, which drive cancer development, or as tumor suppressor genes, which prevent cells from becoming cancerous. He plans to expand his efforts to study how microRNAs function in whole animals, using zebrafish and mice as model organisms. The zebrafish is advantageous because it allows for highly efficient analysis of the consequences of expression of many microRNAs in vertebrate embryos and adults. Studies in mice will allow investigation of microRNA activity in well-established cancer models that closely resemble the human disease.
The office photo is a reminder of an important discovery that has sparked a much broader effort to understand the roles of microRNAs in cancer, but it also tells a larger story about Mendell as a scientist: Research may be his profession, but science plays a role in his personal life, too.
His father, Jerry Mendell, a neurologist at Ohio State University, inspired the teenage Mendell to work in a molecular biology lab. The young Mendell continued to do so through high school and college at Cornell University.
"I loved the lab and knew I wanted basic research to be a major part of my career," Mendell says. He obtained an M.D./Ph.D. at Johns Hopkins, thinking he would practice medicine and perform research. During that time, he discovered proteins that help destroy aberrant RNAs in the cell, beginning his fascination with RNA molecules.
Soon, he shifted gears and decided to focus solely on research. "It was a very difficult decision," he says. "But I realized that I am happiest in the laboratory. While working with patients is extremely gratifying, I knew that in order to perform research at the highest level, I would have to focus 100 percent on science."
Although Mendell is now investigating a broad array of questions related to microRNA biology, he continues to interact closely with family members on several key projects. For example, a recent collaboration with his scientist wife and his father reveals that Mendell's work may eventually help patients. O'Donnell, still at Hopkins, studies animal models of liver cancer, and the senior Mendell studies gene therapy for neuromuscular diseases and develops vectors to deliver genes inside cells. The three devised a plan over Thanksgiving dinner in 2007 to try microRNA gene therapy to treat liver cancer in mice.
The microRNA miR-26a is normally highly expressed in many tissues and keeps cells from proliferating. After the three collaborators discovered that liver cancer cells have reduced levels of miR-26a, they tested whether restoring the microRNA would have an impact. They intravenously injected a specially designed virus carrying miR-26a to mice with liver cancer. The tumors were eradicated. The study was published in Cell in June 2009. "We were very excited to see that the microRNA not only blocked disease progression, but it did so without causing any toxic effects to normal cells in the liver or other tissues," Mendell says.
Mendell's motivation goes beyond finding cures, however. "I am drawn to questions in science that don't fit the textbook model of biology," he says. "When an observation seems to contradict the accepted dogma, it often signals that an opportunity exists to learn something fundamental about how cells work. Ultimately, the greatest satisfaction in science comes from discovering these fundamental truths."