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S3-E17.4 – What Can Single Cell Genomics Teach about Hepatic Regeneration?

Which riddles around hepatic regeneration can we foresee answering in the future as the capabilities around single-cell genomics and its successors continue to expand rapidly?

Professors Scott Friedman and Neil Henderson join the Surfers (including the returning Stephen Harrison) to discuss some truly exciting advances in the basic science and technology of defining, diagnosing, and treating NAFLD and NASH. This conversation focuses largely on questions of how hepatic cells regenerate and what more we can learn about this phenomenon over time as technology improves.

Unlike the first three conversations, whose pace ranged from “rapid-fire” to “hold on, we’re racing”, this conversation goes at a slightly slower pace. It starts with Stephen signing off by discussing how helpful this kind of discussion is for someone focusing primarily on drug development today and congratulating Scott once more on his recent award.

Louise Campbell asks a cautionary question: what if when we replicate the liver’s ability to regenerate tissue, it doesn’t stop but generates more tissue than the liver needs, thereby creating hyperplasia? Scott responds by asking how we can characterize the “magic of regeneration,” that regenerating livers grow to the size they need to be and then stop. His concern is not hyperplasia in itself, but that the regenerating liver will grow more cancer cells. He describes the need to “walk a tightrope” where we regenerate healthy cells but “do not overexcite them to the point where they turn into a cancer,” particularly since some of the same processes inherent in regeneration are also found in cancer cell proliferation. Neil agrees, but also comments on the remarkable plasticity of the liver that you can find a “bad” liver scar, clear the scar and have tissue evolve into functional liver tissue once more. It is conceivable, Neil notes, that we could attain the “Holy Grail” of clearing bad fibrosis and having the liver regenerate itself to normal function.

On the last round of questions, each participant found something truly valuable and/or profoundly interesting in this discussion. Scott describes the general goal as “developing the right treatment for the right cell at the right time in the history of the disease.” He goes on to note that these technologies have helped us learn that the right treatment for a cell in an earlier stage of disease might differ from a later stage, and similarly, the right treatments for two cells at any stage in the disease might not be the same. Neil agrees on the issue and goes on to note the challenge of getting through the voluminous amounts of data being created “but boy is it fun!” Jörn looks from the drug development perspective to note that “individualized pathophysiology” may be necessary to learn why a given drug will work in one patient and not another, but that these tools may enable us to analyze at that level. Louise looks toward these techniques as a way to diagnose earlier when the disease burden is lower on the patient and therapies are less costly and intensive. Neil raised the hypothetical prospect of complex molecular diagnostics that can answer these questions using non-invasive modalities, which sounds like a dream but, at the end of a recent conversation with imaging colleagues, “doesn’t seem like Saturn.” Finally, Roger talks about the idea that this information challenges and simultaneously enriches the concept of longitudinal combination therapy. From this conversation, it seems likely that an F2 patient who has regressed from cirrhosis has differences in cellular structure compared to a newly diagnosed patient with F2 disease. These tools will provide the richness to treat each in the most effective way. Scott wrapped up the discussion by citing work suggesting that when the liver regresses and doesn’t need active stellate cells to make scar, some die…but others simply inactivate. Using Roger’s example, he asks whether F2 therapy after patients regress should focus on inactivated cells or cells that have never activated in the first place, “and we know they are different.”

And with that, an exceptionally energizing and intellectually stimulating episode came to an end.

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