Beth Levine readily acknowledges that the word "autophagy" does not exactly roll off the tongue. In fact, most people have probably never heard of the term, which describes a type of cellular housecleaning that destroys unwanted proteins and organelles. But Levine thinks the word—pronounced "aw-tahf-a-gee"—deserves a prominent place in conversations about cancer, neurodegenerative diseases, and infectious disease. Levine, who is using what she's learned about autophagy to improve treatment of a wide range of diseases, could help make that happen.
Autophagy—which literally means "self-eating"—is a process in which lysosomes devour damaged or unwanted cellular components. Lysosomes, cellular organelles that contain digestive enzymes, perform many housecleaning tasks that are necessary for normal cellular functions. Their regulated destruction of cellular components can also lead to a type of programmed cell death.
Levine's research has revealed that defects in autophagy play a significant role in human disease, contributing to the development of cancer, neurodegenerative diseases, infectious diseases, and, potentially, autoimmune diseases.
"Autophagy has been known to exist since the invention of the electron microscope, but it was largely ignored because there were no tools to find out what it was doing, what molecules were involved," she said. "I got into it serendipitously. The timing was right to take a closer look."
With an M.D. from Cornell University and a residency in internal medicine, Levine also pursued postdoctoral training in infectious diseases and the neurobiology of viral pathogens at Johns Hopkins. From 1994 to 2004, she was Director of Virology Research at Columbia University. "I enjoy clinical medicine, but research affords the opportunity to think creatively, to generate new hypotheses about how biology and medicine work, and to discover new biomedical truths," she said.
While investigating the bcl-2 gene, which prevents cells from committing a type of programmed cell death known as apoptosis, Levine and her colleagues identified the first mammalian autophagy gene, beclin 1. Her lab has since generated evidence that when beclin 1 stops working, a surprisingly wide range of problems can result.
Working in yeast, the roundworm Caenorhabditis elegans, and mice, Levine has shown that beclin 1 is important for preventing tumors. She hypothesizes that lack of beclin 1 activity may also contribute to breast cancer, lung and ovarian cancers, and B cell lymphomas. It also seems to be important for fighting off viruses and bacterial infections and in helping to protect against neurodegenerative and autoimmune diseases and aging.
Levine's lab has discovered many of the ways that cells lose their ability to destroy unwanted proteins and organelles. When these proteins and organelles are not disposed of in a timely fashion, diseases can develop. For example, Levine has demonstrated that the insulin-like signaling pathway often implicated in cancer inhibits autophagy. She has also shown that viral proteins can bind to Beclin 1 and block autophagy. This process may enable viruses, such as Kaposi's sarcoma-associated herpesvirus, Epstein Barr virus, and HIV, to gain a foothold during infection. These mechanisms present potential targets for drug development.
Levine is ready to investigate directly just how much beclin 1 and autophagy influence human health. Ongoing clinical trials at the University of Texas Southwestern Medical Center (UTSW) and other institutions will be valuable resources for Levine as she begins to bring the information she has gleaned in her laboratory into studies with patients.
To test whether defective autophagy contributes to breast cancer, Levine and her colleagues will measure Beclin 1 and autophagy levels in breast tissue biopsies from women who are being followed by physicians at the UTSW's Breast Cancer Working Group who have or are at high risk for breast cancer. Eventually, they expect to begin clinical trials to evaluate whether new compounds that restore beclin 1 expression or activity are effective treatments for patients with breast cancer. The breast cancer drug tamoxifen, Levine said, upregulates beclin 1 expression. "So we know it's possible to upregulate the expression of the beclin 1 gene in cancer, and that's what we plan to do."
Levine is also interested in Beclin 1's role in antiviral immunity. She is trying to understand how HIV might target Beclin 1 so that it can survive in human immune cells. To address this question, she and her colleagues will isolate viral proteins from patients in UTSW's HIV clinic and test the ability of those proteins to bind to Beclin 1. Meanwhile, they will search for chemical compounds that might disrupt this interaction.
Levine and her colleagues also suspect that ineffective autophagy may contribute to autoimmune diseases by interfering with the removal of dead cells, and so they plan to evaluate this possibility in patients as well.
"We're ready to prove that what we have learned in model organisms also applies to humans," said Levine. "If we can make that leap, and enable new treatments for these diseases, then I'll have met my goals."