The Signer Laboratory investigates stem cells at the interface of regenerative medicine and cancer biology. Stem cells reside in many of our tissues and organs throughout life. These rare stem cells have the remarkable potential to regenerate many of the specialized cells in our bodies after they are lost to normal wear and tear, injury and disease. Declines in stem cell function can lead to the onset of degenerative diseases. Overactivation or hijacking of stem cell activity can lead to uncontrolled growth and cancer. By unlocking the mysteries of stem cells, we expect to make breakthroughs that allow us to harness the regenerative potential of stem cells to treat degenerative diseases and identify new therapeutic targets to eradicate cancer.
Stem cells are lost in translation
Translation, the process of protein synthesis, has long been thought of as a housekeeping function, performed similarly by most cells. We broke that paradigm using a new technology that allowed for the quantification of protein synthesis within single cells in vivo. Using this technology we discovered that hematopoietic (blood forming) stem cells in the bone marrow synthesize new proteins much more slowly than other types of blood cells. Furthermore, we determined that low protein synthesis is crucial for maintaining the regenerative activity of hematopoietic stem cells. This was a novel and conceptually important mechanism not previously known to regulate stem cells. Building upon this discovery, it is now known that low protein synthesis is a broadly conserved feature of somatic stem cells that promotes regeneration in multiple tissues. These discoveries, which were published in Nature, uncovered a new world of biology that has set the stage for our current studies.
The science of tidying up
Why do stem cells depend upon low protein synthesis? Recent discoveries from our research reveal that by making proteins slowly, stem cells produce fewer misfolded proteins than other cells. We discovered that even a modest accumulation of misfolded proteins impairs the regenerative activity of stem cells. Misfolded proteins can contribute to the development of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Our discoveries raise the possibility that misfolded proteins may also be at the root of many other types of degenerative, malignant and age-related diseases.
We are currently addressing the fundamental question of how cell-type specific differences in the regulation of protein homeostasis uniquely support stem cell maintenance and longevity, enhance tissue regeneration, suppress cancer, and promote healthy aging.