Jacob Kimmel: belief

Transcript context

…I have many controversial opinions. One of them is that both of these probably in the limit will not be the way that we're delivering medicines in the year 2100. If you think about viral vectors, no matter what, they're always going to be some amount of immunogenic. You're always going to have your immune system trying to fight them off. You can play tricks, you can try and cloak them, etc., but they're always going to have some toxicity risk. They also don't go everywhere. It's not that we have examples of a single viral species that infects every cell type in the body and we just need to engineer it to make it safe. We would have to also engineer the virus to go to new cell types. There's some limitations there. LNPs likewise have some problems. They can go to tons of cell types. That's largely what we're working on. We're super excited about it. But there are some physical constraints. They just have a certain size. They have to get from your bloodstream out of your bloodstream toward a given target cell, and they have to not fuse into any of the other cells along the way. There's a whole gamut they have to run. Ultimately, we're probably going to have to solve delivery the way that our own genome solved delivery. We have the same problem that arose during evolution. How do I patrol the body, find arbitrary signals in the environment, and then deliver some important cargo there when some set of events happens? How do I find a specific place and only near those cell types release my cargo? The problem was solved by the immune system. We have cell types in our body, T cells and B cells, which are effectively engineered by evolution to run around, invaginate whatever tissues they need to. They can climb almost anywhere in the body. There's nowhere they can't get access to, almost. Once they sense a particular set of signals—and they've got a very ornate circuitry to do this, they run basically an AND gate logic—they can release a specified payload. Right now, the way our genome sets them up, the payload they release is largely either enzymes that will kill some cell that they're targeting or kill some pathogen, or some signal flares that call in other parts of the immune system to do the same thing. So that's super cool. But you can think about it as a modular system that evolution's already gifted us. We've got some signal and environmental recognition systems so we can find particular areas of the body that we want to find. Then we have some sort of payload delivery system. I can deliver some arbitrary set of things. I imagine if we were to Rip Van Winkle ourselves into 2100 and wake up, the way we will be delivering these nucleic acid payloads is actually by engineering cells to do it, to perform this very ornate function. Those cells might actually live with you. You probably will get engrafted with them, and they might persist with you for many years. y engineering cells to do it, to perform this very ornate function. Those cells might actually live with you. You probably will get engrafted with them, and they might persist with you for many years. They deliver the medicine only when the environment within your body actually dictates that you need it. You actually won't be seeing a physician every time this medicine is active. Rather, you'll have a more ornate, responsive circuit. The other exciting thing about cells is that they're big and they have big genomes. You actually have a large palette to encode complex infrastructure and complex circuitry. You don't need to limit yourself to the very small RNAs you can get in that might encode a gene or two, or in our case, a few transcription factors. You don't have to limit yourself to this tiny AAV genome that's only a few kilobases. You've got billions of base pairs to play with in terms of encoding all your logic. So I think that's ultimately how delivery will get solved. We've got many, many stepping stones along the way. But if I could clone myself and work on an even riskier endeavor, that's probably what I would do. In a way, we treat cancer this way with CAR-T therapy, right? We take the T cells out and then we tell them to go find a cancer with this receptor and kill it. Is the reason that works that the cancer cells we're trying to target are also free floating in the blood? Is that what it targets? Basically, could this deliver to literally every single cell in the body?…

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