Engineering models of the human gut

Imagine a far future where tailored therapy is the standard, not the exception. In this exciting future, a patient with a condition such as colorectal cancer could visit their physician for a biopsy, and the patient’s own gut cells could be used to build a simplified version of their colon in the lab, a so-called colon-on-a-chip, that demonstrates key relevant characteristics of the patient’s own gastrointestinal tract. About four weeks later, that mature colon-on-a-chip could be used to test and optimize therapies best predicted to improve the outcome for the patient, thus potentially treating their condition more quickly, safely and effectively.

What sounds like science fiction may now be one step closer to reality thanks to an excitingfrom Roche’s Institute of Human BiologyRoche’s Pharma Research and Early Developmentand EPFL’spublished June 13 in the journal Cell Stem Cell. In this work, IHB postdoctoral researcher and first author Olga Mitrofanova and colleagues report developing mini-colons- and mini-intestines-on-a-chip ( image above ), specific types of organoids-on-a-chip models, that capture the cellular diversity, shape and biological response to drug combinations that are observed in human patients. These bioengineered organoids allowed separating the gut’s response to two cancer drugs, showing that they affect distinct cellular compartments. Such detailed mechanistic understanding on an individual level can in the future enable more precise therapeutic interventions.

Major progress in developing powerful new in vitro human model systems - that is, ways to mimic and test human biology and its functionality in the lab - has been made in recent years. Beyond the traditional cell lines and animal models, these include “organs-on-a-chip” and organoids. Organs-on-a-chip engineer cells - often decades-old tumors grown in labs - to seed onto polymer chips in the kinds of shapes that enable drug development experiments (e.g. epithelial barriers), while organoids are derived from stem cells that develop into tissue cultures containing diverse cell types as seen in the body. 

While both systems have key advantages in representing biology, they also have some drawbacks. For example, the organs-on-a-chip enable scientists to make precise measurements, but forcing cells into structure is at the cost of the complexity of biology that ultimately may underlie drug effects. In contrast, organoids leverage the body’s natural developmental processes and show relevant physiology of parts of organs, but they are variable from organoid to organoid and often have atypical cellular organisation and architecture. This makes controlled studies of drugs or other biology challenging.

The recent study now presents an “organoid-on-a-chip” approach, an organ-on-a-chip combined with an organoid, that seeks to overcome these challenges by incorporating aspects of both technologies. It helps adult stem cells to grow more reproducibly into controlled structures closer to natural architecture. Still, they retain the ability to demonstrate biological complexity of the native organ they are trying to represent.

Organoids-on-a-chip are not only more predictable in their development than organoids alone, but they can also be grown and maintained for longer, allowing for repeated tests of potential therapies or studying biological processes that unfold over time. And the longer they grow in the lab, the more similar they become to the biology within our tissues. That similarity extends to the response to drugs that are known to be toxic in people. Mini-colons-on-a-chip captured clinically-seen hallmarks of toxicity and were amenable to sophisticated analysis methods in cases where relevant animal models fall short of elucidating what the drugs precisely trigger.

While this first proof-of-concept recapitulates a healthy gut, IHB researchers continue to work on further expanding the use of these powerful but complex model systems: on technology to make organoids-on-a-chip more accessible to other scientists, and on biology to incorporate key cells types (e.g. immune cells) or disease states (e.g. tumor outgrowth).

Even when these tweaks are made, the system won’t be the best technology for every scientific question in drug development. For example, given their bespoke nature and the limited throughput, the models won’t be the tool of choice for high-content screening of hundreds of drug candidates - however, they will be great for testing and assessing potential new drugs for safety and efficacy and understanding the drug’s mechanism of action. Traditional drug development approaches have limitations that organoids-on-a-chip technology aims to overcome. For instance, animal toxicology studies can reveal species-specific biology, which may not translate well to humans. Organoids-on-a-chip can help bridge this gap by providing a more accurate human model. Additionally, early clinical studies have limited capacity to explore mechanistic hypotheses, a constraint that these new organoid models may help to address by allowing for more detailed and controlled testing.

Already, these bioengineered organoid models are being deployed to study multifactorial diseases like colorectal cancer and inflammatory bowel disease (IBD). And the same basic technology should work well for modeling other organs, too, that have similar epithelial structures, such as lung and breast, which has exciting implications for expansion of application into other diseases such as COPD and breast cancer.

About the image (at top):

Researchers were able to generate in vitro models of the human gut that showed remarkable similarity to the native organ in terms of shape and biological complexity. The histological section shows how the bioengineered human mini-colon-on-a-chip mimics the natural anatomy of the gut epithelium (labeled in pink) and physiologically important mucus production by secretory cells (labeled in blue).