Why haven't organoids solved all of drug discovery?

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Primers<br>Why haven't organoids solved all of drug discovery?<br>5.8k words, 26 minutes reading time

Abhishaike Mahajan<br>Jul 28, 2026

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Thank you to Jimmy Sastra and Kitchener D. Wilson for discussions relating to this piece. All opinions are my own.<br>This essay is the first of three covering organoids. The full set is:<br>Why haven’t organoids solved all of drug discovery?

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What are organoids anyway?

Why haven’t organoids solved all of drug discovery?

The problems with organoids<br>The reproducibility of organoid work is (likely) abysmal

Many therapeutic knobs are not exposed in organoids, and it is difficult to add them in

An organoid’s relationship to age is strange

Conclusion, and what are organoids good for then?

What are organoids anyway?

If someone placed a gun to the side of your temple and asked you to correctly define what exactly an “organoid” is, or else they’ll shoot, you may get a little nervous. The whole concept is something, you suddenly realize, you never quite understood. It’s more of a you-know-it-when-you-see-it thing, nobody in their right mind would ever ask for a clear definition, but you forgot to account for those who are not in their right mind. Desperately, you rack your brain for details. It’s an aggregate of cells, right? You stammer this out, tack on ‘it’s three-dimensional too!’, and stare at your antagonist expectantly. They consider your answer, and squeeze their hands.<br>If we were to interview your terrorizer later on, they would sheepishly admit that your answer is not the worst one they’ve heard. It really does encapsulate the many forms that organoids may take. Unfortunately, your given definition would also welcome blood clots, teratomas, and biofilms, all of which are indeed aggregates of cells arranged in three dimensions, but none of which would be considered an organoid by anybody on the planet.<br>You should not feel bad about this. In fact, you are in good company. The organoid field as a whole is not known to have particularly useful definitions.<br>One attempt at a definition comes from a 2014 Science review titled ‘Organogenesis in a dish: modeling development and disease using organoid technologies’, which defined an organoid as having the following traits: it is derived from either stem cells or organ progenitors, contains multiple organ-specific cell types, and recapitulates some type of organ-specific function. This feels more accurate, and swiftly removes blood clots, teratomas, and biofilms from the table.<br>Importantly, the organ-specific function bits of the definition help clarify something important: spheroids are not the same thing as an organoid . What is a spheroid? Here’s a useful infographic:

You, at the very start, described a spheroid.<br>Well, that’s that, right? Organoids are simply spatially complex, multicellular three-dimensional aggregates.<br>But we’re still missing some pieces. A 2023 Stem Cell Reports paper titled ‘Organoids are not organs: Sources of variation and misinformation in organoid biology’ has the following complaint about the particular definition stated above:<br>As a generic definition of an organoid, this fails to identify the distinctions between pluripotent stem cell [PSC] and tissue stem cell-derived [TSC] organoids.

The authors go on to say why this matters, but their explanation is dense and orthogonal enough to the point that we needn’t bother teasing out the details here, though we will later. What is important to understand is that PSC-derived organoids and TSC-derived organoids are doing fundamentally different things at the biological level, recapitulating different stages of tissue biology, and yet the word "organoid" is asked to contain both of them.<br>So: organoids are three-dimensional, multicellular, spatially organized, self-assembling structures derived from [cells] that recapitulate some aspect of [biology], though what cells and what biology will vary based on what the actual ‘organoid’ system is.<br>With regard to a definition, this is the best we can do. It is not very good, but it is good enough grounding to start discussing a very vital question.<br>Why haven’t organoids solved all of drug discovery?

There is a reasonable reaction one may have upon learning that organoids exist: why aren’t these being used all the time?<br>These are human, I repeat, human tissues that are lying in a dish, ones that are seemingly able to roughly organize themselves to semi-resemble complex, multicellular tissues. Why do we use mice, or any animal, at all? Hell, why do we even have clinical trials? Let’s just spin up a few hundred of these things and throw drugs at them. Get the FDA on the phone! It’s an emergency!<br>Yes, maybe the failure rate of this brave new endeavor will be high, but it’s a risk we should be willing to take. It’s not like we were doing so well before. After all, 99.6% of Alzheimer’s drugs fail, oncology...