In a groundbreaking study that could have significant implications for organ transplantation and emergency healthcare, researchers at the Wyss Institute for Biologically Inspired Engineering at Harvard University have discovered that a non-addictive pain relief drug, SNC80, could play a pivotal role in preserving cells and organs. Published in eLife as a reviewed preprint, this study offers compelling evidence that SNC80 can rapidly induce a sleep-like state in cells and organs, a process termed biostasis, which significantly slows down biochemical and metabolic activities while maintaining cell and tissue viability.
The conventional method for preserving cells and organs for transplantation involves lowering their temperature to slow down metabolic processes, mimicking hibernation. However, this approach, known as static cold storage, often results in tissue damage, and the technology required for maintaining viable cells and tissues is not always practical in emergency or resource-limited situations. Megan Sperry, the lead author of the study, highlights the urgent need for improved methods of tissue and organ preservation that can be quickly and safely reversed, ensuring that major tissue functions return to normal within 24 hours.
In their quest for a solution, the research team conducted a comprehensive review of scientific literature to identify drugs that could potentially slow metabolism and mimic the effects of hypothermia or hibernation. SNC80, developed as a non-addictive analgesic acting on the delta opioid pathway, emerged as a promising candidate due to its hypothermia-inducing properties and protective effects against spinal cord blood flow obstruction.
Initial tests on tadpoles revealed that SNC80 could halve their swimming activity within an hour, with rapid reversibility upon drug removal. Additionally, the drug significantly reduced oxygen consumption and had a profound, yet reversible, impact on heart rate. These promising results led to further exploration of SNC80’s clinical potential.
The researchers then tested SNC80 on a donor pig heart, using a portable, oxygenated preservation device. The drug effectively reduced the heart’s oxygen consumption by more than 50% over six hours, with a swift recovery of normal oxygen levels and pulse rates once blood flow was restored. The successful application of SNC80 in inducing biostasis in human cells was also demonstrated using organ-on-a-chip models of the gut, where a six-fold reduction in metabolism was observed over 48 hours, gradually returning to normal after the drug was removed.
Despite these promising findings, the researchers caution that further validation is needed before SNC80 can be utilized clinically. Concerns arise from the drug’s side effects, including seizures observed during pre-clinical trials, which halted its development. The team is addressing these concerns by developing a new, non-opioid analog called WB3 for future studies. Additionally, the efficacy and safety of SNC80 will need to be confirmed in post-transplantation scenarios.
Donald Ingber, senior author and Founding Director of the Wyss Institute, underscores the potential of SNC80 to revolutionize organ transplantation and emergency healthcare. By enabling a rapid, reversible state of suspended animation through injection, SNC80 could extend organ viability, improve survival rates in trauma and acute infection cases, and open new avenues in military, space exploration, and civilian emergency response.
This research not only illuminates the path toward enhancing organ preservation and trauma care but also exemplifies the innovative spirit of combining pharmacology with biologically inspired engineering to solve critical healthcare challenges.
Exploring Small Molecules for Biostasis
Tissue and organ loss due to trauma, disease, and injury pose significant challenges in the medical field, accounting for a substantial portion of human ailments and a staggering $400 billion in annual medical costs. The current standard for organ preservation involves static cold storage, a method that, while effective in the short term, can compromise the integrity of grafts over time. Additionally, inducing a state of biostasis, characterized by slowed metabolic and physiological processes, has shown promise in improving cell and organ survival for transplantation. Various approaches, including hypothermia and ex-vivo machine perfusion, have been employed to achieve this, but they come with their own limitations.
Recent advancements in the field have explored novel strategies to induce metabolic suppression for organ preservation, aiming for rapid inducibility and reversibility to mimic natural states like hibernation or torpor. A promising avenue involves the exploration of small molecules with unintended side effects, such as SNC80, originally developed as a pain reliever. SNC80 has shown potential in inducing hypothermia and protecting against spinal cord ischemia in rodent models.
In a groundbreaking study, researchers sought to investigate the broader effects of SNC80 on tissue metabolism and physiology. Utilizing Xenopus laevis embryos and tadpoles as models for drug screening due to their small size and permeability to small molecules, the study administered SNC80 at elevated levels to explore its off-target effects, particularly hypometabolism.
The findings of this study shed light on the potential of SNC80 and similar small molecules in revolutionizing tissue preservation techniques. By inducing a state of biostasis, these molecules could offer a promising solution for extending the preservation times of organs and tissues, addressing a critical unmet need in various medical applications. Moreover, the rapid inducibility and reversibility of this approach hold significant promise for its clinical translation, particularly in resource-limited or trauma triage settings where conventional methods may be impractical.
While challenges and further research remain, including optimizing dosage levels and understanding the full scope of the molecular mechanisms involved, the exploration of small molecules for biostasis represents a paradigm shift in tissue preservation strategies. With continued investigation and refinement, these innovative approaches have the potential to save countless lives and alleviate the burden of organ shortage in transplantation.
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