Where have organoids actually been useful?

This essay is the second of three covering organoids. The full set is: Why haven’t organoids solved all of drug discovery? Where have organoids actually been useful? [Unreleased] Introduction In my last essay, I spent a few thousand words cribbing about how most organoid work feels literally incapable of leading to anything useful. This was a lot of fun, but despite all of their issues, it’d be a lie to say that the sum impact of organoids has been zero. In truth, they’ve played a significant role in the stories of some scientific triumphs—at least according to papers—and it can be a fun exercise for us to dissect them. What are these triumphs? And how accurate is the usual telling of them? All this, and more, is the subject of this essay. We’ll start with the most obvious settings, and slowly work our way to the stranger applications. The success stories Identifying which cancer patients will benefit from chemotherapy This one is pretty straightforward. How does chemotherapy work? Nearly all chemotherapies—paclitaxel, cisplatin, doxorubicin—work by futzing with the interior of individual cells. Paclitaxel jams the microtubules, cisplatin crosslinks the DNA, doxorubicin wedges itself between base pairs, all of which are meant to prevent the damn thing from dividing. Terrible news for a cancer cell, also terrible news for every other cell, but the net impact of it all is fine since most of your cells aren’t constantly dividing. Which is to say: chemotherapy acts via a cell-level knob, the level at which organoids are as good as any other in vitro system. So it should not surprise you that this is precisely where organoids have posted their least ambiguous wins. The foundational result is a 2018 Science paper, ‘Patient-derived organoids model treatment response of metastatic gastrointestinal cancers’. The authors built a biobank of organoids from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients. The authors then screened a library of 55 chemotherapy agents against the organoids and compared the results to what actually happened to the patients—who, importantly, had been enrolled in phase 1/2 trials, so there was a real clinical answer key against which to grade the organoids. The concordance was startling: 100% sensitivity, 93% specificity, 88% positive predictive value, and 100% negative predictive value. Holy shit, right? Yes, it wasn’t perfect-perfect across the board, but it did meet perfection on the last value: identifying non-responders. A 2019 Science paper found a similar result for irinotecan, another chemotherapy, in metastatic colorectal cancer. Chemotherapy isn’t traditionally considered precision medicine, but there is known heterogeneity in patient response, and being able to predict it should theoretically allow us to spare millions of cancer patients from a toxic drug that will functionally do nothing for them. This is cool work, but it’s also so within the realm of ‘duh, you’d expect organoids to do this well’ that it probably isn’t worth discussing much further. Instead, let’s consider two likely follow-up questions you have. First, was the organoid bit really necessary? For that matter, what does a tumor organoid even look like? Isn’t it just a blob of tumor cells? What organ-specific function would there be? So…isn’t a ‘tumor organoid’ an oxymoron? Cancer spheroids exist, sure, but surely nothing more. It’s a good point. To answer the more basic question: a cancer organoid inherits its organoid-ness from the organ the cancer is a cancer of. Which is to say: a colorectal cancer organoid looks an awful lot like a typical colorectal organoid, just with messed up internals—a fact that the authors of the aforementioned irinotecan paper demonstrated. So yes, tumor organoids are a coherent concept. But was the organoid part actually needed? Would a simpler spheroid not have done the same thing? In fact, it did. In a 2019 Scientific Reports paper, a spheroid made up of just dissociated ovarian tumor cells produced the following result across 44 patients: 89% accuracy, and all 32 ovarian cancer patients it identified as responders went on to respond to the tested chemotherapy. Hmm. We’ll come back to this. Moving on to the second question: if organoids nail chemotherapy response this cleanly, is this part of standard oncology care? It is not. And somebody has tried: the authors behind the irinotecan result ran a prospective feasibility trial, concluding that ‘patients that received organoid-informed treatment did not experience clinical benefit.’ Strange! Why is this? Well, they do note that they could establish organoids from only 57% of patients, and it took about ten weeks from tissue to readout. You could imagine the problem here is the ten weeks bit; by the time your organoid is ready with a treatment recommendation, the cancer has mutated to an entirely new state. But the fun part about spheroids is that they are much easier to grow! The aforementioned spheroi