Session 11

Detection of cancer at an early stage when they are still localized improves patient response to medical interventions for most cancer types. Yet biomarkers shed from early lesions are limited by fundamental biological and mass transport barriers – such as short circulation times and blood dilution – that limit early detection thresholds. I present work on synthetic biomarkers, which are an emerging class of diagnostics that deploy bioengineered sensors inside the body to query early-stage tumors and amplify disease signals to levels that could potentially exceed that of shed biomarkers. I discuss strategies that harness dysregulated protease activity to amplify detection signals, employ tumor-selective activation to improve specificity, and leverage natural processing of bodily fluids (e.g., blood, urine, proximal fluids) for easy detection. These advances will be presented in the context of early detection of acute transplant rejection, and response and resistance to checkpoint blockade immunotherapy. Finally, I discuss work on logic-gated synthetic biomarkers for programmable immune sensing. 


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Brain aging leads to cognitive decline and is the main risk factor for sporadic forms of neurodegenerative diseases including Alzheimer's disease. While brain cell- and tissue-intrinsic factors are likely key determinants of the aging process recent studies document a remarkable susceptibility of the brain to circulatory factors. Thus, blood borne factors from young mice or humans are sufficient to slow aspects of brain aging and improve cognitive function in old mice and, vice versa, factors from old mice are detrimental for young mice and impair cognition. In trying to understand the molecular basis of these observations we found evidence that the cerebrovasculature is an important target and that brain endothelial cells show prominent age-related transcriptional changes in response to plasma. We discovered that plasma proteins are taken up broadly into the brain and that this process various between individual endothelial cells and with aging. We are exploring the relevance of these findings for neurodegeneration and potential applications towards therapies.

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Human limitations in natural regeneration can dramatically affect a patient's life, such as after limb loss. Axolotl salamander limbs that are anatomically similar to human limbs, but they can perfectly regenerate throughout life. Understanding how this happens may provide important clues necessary for future therapeutic approaches. While most research has focused on the site of injury, we have discovered that cells throughout the axolotl's body activate and proliferate following amputation. This process of systemic activation is akin to what other researchers have discovered to happen in mice following a local injury. However, mice do not go on to regenerate entire limbs. We will present data demonstrating that some of the molecular mechanisms that enables systemic response is mice and shared with axolotls. Elucidating how the systemic response occurs in axolotl will be key to understanding how cells are initially systemically activated, while only those at the site of injury are converted to blastema cells, those cells that are the building blocks for the new limb. Our unpublished work shows that innervation at distantly-responding sites is critical for the systemic injury response in axolotls. This work has led us to consider molecular factors derived from nerves as stimulants for activation pathways in tissue-specific progenitor cells residing throughout the body. A nerve conduit for the response contrasts with the circulation conduit implicated in mouse, raising questions about how information is transmitted throughout the body in super-regenerators versus animals with more limited natural regenerative abilities. We hope this work will lead to both molecular insights as well as theoretical insights about the differences between species when considering regeneration and, ultimately, how human regeneration might be augmented.