Pathways to New Discoveries

by Krista Weidner

Jon Oatley (photo by Steve Williams)

Jon Oatley keeps a notepad next to his bed, so that at 3:00 a.m., when he wakes from a dream about stem cells, he can jot down his ideas. “Something will pop into my head and right away I’ll draw or write it down,” he says. “My wife thinks I’m crazy, but I think if you’re a scientist dreaming about science, you’re in the right field.”

Embryonic stem cells are like master cells that contain all the information needed to create almost any type of cell in the body. During fetal development, these cells differentiate, or change into specific cell types. In doing so, they give rise to the entire body, including the stomach, lungs, and so on. In adults, stem cells also exist at various places within the body to repair damaged tissues, and they constantly regenerate, or self-renew, to keep organs and tissues functioning throughout a lifetime.

Stem cells differ from other cells in that when they divide to form specific types of cells, such as muscle cells, red blood cells, or brain cells, they also make a “carbon copy” of themselves, thus maintaining a kind of “immortality.” The carbon-copy cells maintain the original stem cell identity.

Oatley focuses on spermatogonial stem cells (SSCs), which are found in the testes and allow for continuous production of sperm. “SSCs are responsible for male fertility,” he says. “A normal man produces fifteen hundred sperm with every heartbeat. We know from rodent models that if you mutate the pathways that regulate stem cell activity in the testes, the mice become infertile.”

Oatley and his research team are interested in how stem cells function and how they’re affected by their surroundings. All cells have receptors on their surfaces, and when a hormone or protein binds to those receptors, it elicits a signal within the cell, which in turn spurs dozens of proteins into action. Some of those proteins bind to DNA and change expression of specific genes. “It’s a huge puzzle of proteins interacting and signaling and changing things and communicating,” Oatley says. “I’m constantly drawing arrows between proteins in a cell to figure out the pathways that result in cellular changes.”

Oatley aims some of his work at solving human male infertility problems, but it’s a minor interest. “Male infertility isn’t a big problem,” he explains. “Roughly 20 percent of reproductive-age couples have fertility problems, but only about half are due to males. And about half of those 10 percent result from obstructions in the reproductive tract, not a lack of sperm production.”

Image of a mouse testis (photo courtesy of Jon Oatley lab)The blue strands in this image of a mouse testis provide evidence that transplanted stem cells regenerated sperm production and restored fertility to a previously infertile mouse. The blue coloration results from a trait of the transgenic donor mouse, which has a special gene that turns his cells blue under special treatment. The technique of testicular stem cell transplantation holds promise for men who have become infertile due to treatment for cancer and other diseases. Current practice has men store semen for possible in vitro fertilization later, an expensive and not always reliable technique. Translating the mouse techniques to humans may provide a means to reestablish natural fertility by harvesting stems cells before treatment and reinserting them later, after the harmful effects of the cancer therapy have subsided. Oatley’s primary biomedical research—the work that keeps him sketching pathways in the wee hours—is using spermatogonial stem cells as a model to understand general stem cell biology, which could lead to advances in the treatment of diseases. He and his research team hope that what they learn about stem cells in the testes will also hold true for stem cells in other tissues. They’ve already found mechanisms and pathways in SSCs resembling those that function for neural stem cells in the brain. Photo courtesy of Jon Oatley lab

Because stem cells keep tissues functioning throughout the body, stem cell failures cause degenerative disease. Parkinson’s disease, Alzheimer’s disease, and liver failure can all be tied to stem cell failure. If Oatley can pinpoint the mechanisms that control how a stem cell continuously renews itself, he may be able to learn what causes those mechanisms to fail. Then he can set out to prevent that failure and, thus, degenerative disease.

Oatley is also interested in what happens when stem cells self-renew out of control to form tumors. With funding from the National Institutes of Health, he and his team are researching stem cells’ ability to either self-renew or differentiate into another cell type. “When a stem cell self-renews,” he explains, “it’s making a copy of itself to maintain the stem cell pool. When it differentiates, though, it ceases to be a stem cell and develops into a specific type of cell. We’re looking at the molecular mechanisms that tell a stem cell to go down a pathway of differentiation or self-renewal. When self-renewal becomes overstimulated, it results in a tumor. Essentially, a tumor is a ball of self-renewing, dividing cells.”

Oatley is particularly interested in a type of testicular cancer caused by tumors of germ cells, or reproductive cells, in the testes. “It’s always been believed that these tumor-forming testicular germ cells existed in the embryo and became trapped at an embryonic state, even after birth. Then, later in life, somehow they got kick-started and began forming tumors. We have evidence that the stem cell population in the testes retains some of the characteristics of the embryonic germ cell. Those stem cells are always walking a fine line between differentiation and self-renewal, so we think just one mutation in a key gene could cause them to revert back to that embryonic-like state and form a tumor.”

Melissa Oatley (photo by Steve Williams)

Melissa Oatley, senior research associate, keeps the lab running and oversees the graduate students and research team. She tracks the progress of one research technician, two graduate students, one postdoc, and six undergraduates. Together, Melissa and Jon do the research on ideas her husband feels are too “crazy” to assign to students.

In their work with mice, Oatley and his colleagues are optimistic about a protein called ID4, which stimulates stem cells to self-renew. They found that when they mutate ID4, stem cell self-renewal is impaired and tissue failure results. Consequently, they believe the opposite could be true: if ID4 is overstimulated, stem cell self-renewal will spin out of control to form a tumor. Their hypothesis is supported by the fact that ID4 is present at extremely high levels in cases of human testicular cancer.

“What’s really interesting about this,” he says, “is that ID4 protein is involved not only in testicular cancer but in other cancers throughout the body. Its expression is very high in brain and breast cancers. In fact, ID4 controls the expression of the same gene for which we screen humans to determine susceptibility to breast cancer. As we continue to explore ID4’s relationship with stem cells, we hope to find that it’s involved in stem-cell-derived tumors in all kinds of tissues.”

One of Oatley’s goals is to zero in on the mutations that cause ID4 expression to “go haywire.” The biomedical implications could be far reaching. For example, newborn infants could be screened for those mutations. By simply testing a skin cell from a newborn, doctors could determine if the ID4 mutation is present, and then know if that child will be more susceptible to certain types of cancers. Predicting the possibility of tumors later in life is useful because some cancers can be managed by early diagnosis. If susceptibility is high, doctors can start screening much sooner and remove any initial tumor cells that form.

Stem cells are considered immortal because of their ability to self-renew. But it turns out they can’t do it alone. “It depends on the support system that surrounds it,” Oatley says, “and when that support system fails, the stem cell fails. We call this support system a niche microenvironment, and this is our new area of investigation.”

A stem cell in any tissue resides in its own niche microenvironment of specific growth factors and architectural support that promote the stem cell’s survival and activities. As long as a stem cell is maintained in a young and adequate niche microenvironment, it will remain immortal—it will divide forever. But, if that support fails, then the stem cell fails. Oatley has found that in aged animals it’s the failure of the support system that causes degeneration.

“Now we’re trying to figure out what’s important about these niche microenvironments that causes the stem cells to do what they do. In degenerative diseases, the evidence shows that the support cell population, or the niche microenvironment, fails. This is exciting because if we can figure out how to rejuvenate that support cell population, we can restimulate the stem cells to kick back into action.”

In the laboratory, Oatley and his research staff work with mice to search for a gene or protein that’s involved in the stem cell niche microenvironment. They insert, knock out, or mutate certain genes or proteins to observe the effect on the mouse’s stem cell population and its support system. “If we find something we can lock down and prove beyond a shadow of a doubt that it’s a pathway that controls a mouse’s stem cell biology, we then move on to other species,” he says.

Oatley's research team (photo by Steve Williams)

Oatley’s esearch team, from left to right: Rebecca Crouse, Karen Racicot, Jon Oatley, Amy Kaucher, Carlos Rojas, Melissa Oatley, Dongwon Kim, Suzanne Reding, and Elizabeth Cloninger.

Oatley considers himself a discoverer in the scientific process. “I tell undergraduates that we’re on the ground floor of university research. We’re learning how a stem cell works and identifying genes, proteins, and pathways. I consider it my mission to encourage undergraduates to go into science because I don’t see the next generation of scientists emerging in the United States. I tell students that if they want a career where every day they can ask a new question and then design an experiment to answer that question, they should go into science. Every day there’s the possibility for that breakthrough. Ninety percent of what they try won’t work, but if that other 10 percent results in new ways to treat or even cure a disease and improve human health, it’s all worthwhile.”