Thread by @gwsuperfan

Since people are going gaga over the Vertex Pharma T1D stem-cell announcement yesterday, here's a quick review of where we are, and how we got here: 🧵👇

Islet transplants have been happening for more than two decades: pubmed.ncbi.nlm.nih.gov/10911004/

We've been able to make islets and beta cells from stem cells for quite a while, too. Here's a review article from 2012 (yes, almost a decade ago) summarizing progress on stem-cell derived beta cells up to that point: ncbi.nlm.nih.gov/pmc/articles/P…

It's true that we've gotten better at it over time. Human embryonic stem cells are no longer required (although some groups/labs/companies are still using them). Liver cells were being transdifferentiated into insulin-producing cells as early as 2005: pubmed.ncbi.nlm.nih.gov/16890895/

iPSCs can be derived from a number of tissues, and the techniques to get them to turn into cells that make insulin are being continually refined. So hESCs (and the moral issues that go along with their use) are no longer needed. …nslational-medicine.biomedcentral.com/articles/10.11…

I don't mean to imply that it's trivial, or that there's not still room for improvements in the process, but making cells that can & do make insulin in response to glucose hasn't been dark wizardry or deep magic in a while.

The problem at this point is **keeping those cells alive** when they're implanted in a human with #T1D. *THAT* is the challenge.

The new cells need to be protected from the same autoimmune response that killed off the original ones while still allowing enough blood flow to provide nutrients and oxygen to keep them alive. There are a number of techniques under investigation to achieve this.

Of course, there's always the "sledgehammer" approach of broad immunosuppression, but that comes with a lot of negatives. It leaves patients susceptible to infections from any number of pathogens, and also carries a risk of developing cancer.

So, we're left with other approaches. #Teplizumab shows promise at delaying #T1D progression, and is more targeted, but I'm not aware of any investigation of whether it would be effective at providing protection for transplanted beta cells.

There are also hints of what's going on immunologically that can be gleaned from immune therapies for various cancers. In fact, developing T1D (and/or other autoimmune diseases) is a known side effect of many cancer immunotherapies.

Lots of cool research is being done along these lines- including inducing over-expression of PD-L1 in Human Islet-like organoids (HILOs) in order to protect them from the immune system: pubmed.ncbi.nlm.nih.gov/32814902/

But in the short-term, the most promising approach to protecting new stem-cell-derived insulin-makers is probably encapsulation. Macro-encapsulation puts the whole mass in a pouch. While promising, getting the material the "pouch" is made of to be both sufficiently...

impermeable to the immune cells and still let enough oxygen-carrying red blood cells and plasma that contains nutrients to keep the little insulin-makers inside alive is HARD. We ain't there yet.

Microencapsulation offers another promising approach to protecting the transplanted b-cells as well pubmed.ncbi.nlm.nih.gov/30748094/

But as of right now, none of these approaches are anywhere near ready for use in humans, so while we can make insulin-making cells in a lab, and implant them into people, if they are to survive, we're stuck with the "sledgehammer" approach of broad immunosuppression.

This is essentially what happens with a pancreas transplant, and it's been demonstrated successfully in humans by a number of research groups and companies.

The big hurdle is the need for immunosuppression. We can make b-cells or even whole islets. We can transplant those cells into people. What we CAN'T do is keep the body from killing them without turning the immune system (largely) off.

So, when Vertex announces that they've successfully transplanted insulin-producing cells into a person, and that those cells are making insulin, that's great! -BUT- if immune suppression is still needed, it's not (on the surface at least) anything new.

We've been here before. Several times.

Call me when immunosuppression is no longer required (or at least when it's much more narrowly targeted).

Note: this is intended to be a broad, 30k-foot overview, not an in-depth discussion. If you read this, and I've got something MAJOR wrong, let me know.

/fin