When Marie Csete says something's in the air, she means it.
After two decades as an anesthesiologist, Csete wrote a Ph.D. thesis that overturned conventional wisdoms about oxygen's effect on stem cells. For decades, scientists have placed their tissue samples in the "room air" of a laboratory. Csete showed, however, that what researchers were taking for granted as harmless was in fact toxic. "Room air is 21% oxygen, but the oxygen level in the body tissues is about 3%," she says. "By leaving their Petri dishes in room air, scientists have been systematically poisoning the cells in their cultures."
Her findings about the toxic effects of room air on stem cells rankled some. "Not everyone wanted to hear about it," says Csete, who took home the Clauser Prize for best Ph.D. thesis at Caltech in 2000. "It requires an entire rethinking of the physiological structure of our laboratories."
Today Csete is also rethinking embryonic development. In a study funded by the Keck Foundation and conducted in partnership with Michel Maharbiz at the University of Michigan, she is challenging the assumption that protein gradients are the starting point for establishing body "patterning" of an embryo. Csete argues, instead, that gas gradients - levels of oxygen in the developing embryo - are the cues used to set up protein gradients. These ideas put oxygen as a more fundamental cue to embryonic development and patterning than previously acknowledged.
For Csete, who divides her time between Emory's liver transplant team and the stem cell biology laboratory, understanding the role of oxygen in embryonic and stem cell development holds promise for a range of clinical applications:
* Exploring how stem cells age.
The free radical theory of aging is a long-standing theory of cellular aging. Oxygen radicals are major causes of cellular damage over time. The oxygen toxicity to cultured stem cells may provide a clue to cellular aging. The Csete lab is evaluating the effects of antioxidants by studying muscle stem cells from mice with deletions or over-expression of these genes, originally part of a program project at the University of Michigan. Although none of the antioxidant manipulated stem cells captures the full aging story, taken as a set they point to new targets that can help to preserve muscle mass with aging.
* Relieving pain.
Together with Markus Klass, an Assistant Professor of Anesthesiology at Emory, Csete is studying stem cells as a therapy for pain. In tests on rats whose sciatic nerves had been constricted, causing a verifiable pain response, Csete and Klass found that bone-marrow transplants (injected into a tail vein) led to a dramatic change in pain responses. "After ten days, all of the animals that did not receive transplants continued to be in significant pain, but the animals that received the transplants were statistically not different from pre-op," Csete says. "This was not a reduction in pain; it was a reversal." Again oxygen is part of the story: stem cells are known to find their way to sites of injury (such as the nerve constriction) by following cues set up by low oxygen at the injury site. Klass and Csete want to see the analgesic effects of stem cells used to identify novel drugs for the treatment of pain.
* Combating fetal alcohol syndrome.
As the founding director of Emory's core facility for embryonic stem cell research, Csete works to understand and treat fetal alcohol toxicity, the most common preventable cause of mental retardation in the United States. (Alcohol also exerts some of its effects through oxidative stress.) Using human embryonic stem cells as a "test bed" for ethanol's effects on the embryo, Csete found that before ethanol causes massive amounts of cell death (apoptosis), it first causes overwhelming undifferentiated stem cell proliferation and neurogenesis. In other words, the massive cell death that scientists have seen as the major feature of fetal alcohol toxicity may actually be a secondary effect of excessive cell growth. Csete says she wants to make these findings "clinically relevant" by adding nicotine to the mix, "because these substances are co-travelers." She hopes this research will lead to new treatments for alcohol-exposed embryos. Human embryonic stem cells are ideal for understanding not only toxicity to embryos but also for developing tools to protect vulnerable embryos.
* Detecting sepsis.
In collaboration with Georgia Tech researchers Bill Hunt and MD/PhD student Chris Corso, Csete and her Emory team are adapting a non-invasive, bedside, "real time" device for early detection of sepsis, the massive organ failure that causes thousands of hospital deaths each year. Again oxygen is center stage: early physiologic responses to infection include a massive rerouting of blood flow, and thus organ systems respond to changing oxygen levels in ways analogous to those of stem cells. When Hunt's innovations in acoustic wave technology appeared to offer an ideal tool for shortening the time it takes to diagnosis sepsis, his lab developed a prototype for a protein-detecting 'breathalyzer' capable of identifying the subtle physiological changes that precede sepsis as a syndrome. Soon the breathalyzer will be tested in patients. Says Csete: "This is an engineering application that in some ways is skipping the lab altogether." She predicts the device will help hospitals gain "a better handle on sepsis without resort to invasive diagnostic tests."
For Csete, Emory remains a great place to work because of its openness to new ideas - especially those that are controversial or threaten scientific conventions. She welcomes the university's commitment to protecting the time of its clinician-scientists, so that they can stay in their labs when necessary. And as the co-director of Emory's MD/PhD program, Csete adds that students help make the challenges of her profession worthwhile.
So do the patients. Says Csete: "Our patients are incredibly sick. It's a constant inspiration to come back here to the lab and to make something better for them." Maybe change really is in the air.