Our mission is to discover the origins of blood disorders and cancer. To do this, we study blood-forming stem cells. These are very rare cells in the bone marrow that have two unique superpowers: they can become any other type of blood or immune cell and they self-renew (make more of themselves). Throughout life, stem cells keep us healthy by regenerating all our blood and immune cells.

The problem is stem cells’ ability to self-renew can go awry. When stem cells don’t self-renew enough, tissues don’t appropriately regenerate and we develop degenerative diseases, including anemia, bone marrow failure and immune dysfunction. On the flip side, when stem cells self-renew too much, or when the wrong type of cell hijacks self-renewal, it can lead to cancer. Understanding how stem cell self-renewal works empowers us to treat these diseases at their root.

Our breakthrough research discovered blood-forming stem cells produce protein slower than other types of cells. Proteins are workhorses carrying out specialized jobs within cells. When proteins are produced too quickly, it leads to errors that cause them to malfunction, which severely impairs stem cells. By strategically targeting these pathways we improve stem cell fitness, enhance tissue regeneration, and suppress cancer. By leveraging normal stem cells in our scientific process, we are unraveling the origin of diseases that is leading to the development of novel therapies to improve patient outcomes.

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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.

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Why are stem cells so sensitive to increased protein synthesis? Recent discoveries from our research reveal that 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 blood diseases.

Picture1Picture4Keeping stem cells fit
How do stem cells stay fit? A new breakthrough from our lab published in Cell Stem Cell, revealed that cell culture rapidly and massively increases protein synthesis within blood-forming stem cells. This enormous protein stress contributes to the inability to grow and expand these stem cells outside the body, which has limited their availability for patients that could benefit from stem cell transplants. To cope with this stress, stem cells activate the gene Hsf1 , which helps restore equilibrium and maintain stem cell fitness. Small molecules that super-activate Hsf1 enable us to grow high-quality stem cells for prolonged periods. We also found that Hsf1 gets activated within stem cells during aging to keep them fit throughout life. These discoveries will hopefully improve clinical outcomes for patients in need of stem cell transplants and could one day be leveraged to prevent blood disorders and boost immunity in older adults.

We continue to address 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.


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