“The dream of the organ-on-chip field is to create personalized tissue models for every organ and for every individual with a disease. These models can then be used to test drug efficacy in a patient-specific manner.”
Our ultimate aim is to develop personalized tissue models of disease to improve our understanding of disease mechanisms and test novel treatments for both complex and monogenic disorders.
Our starting point will be iPSC cells from individuals with a specific genetic background, either patients or Lifelines participants with a particular polygenic risk score. These iPSC cells can then be differentiated into different types of tissues. Initially, we have focused on the gut and developed models for celiac disease (https://tinyurl.com/k3xc424y). We will challenge these mini-guts with gluten peptides, cytokines and other (microbial) metabolites associated with celiac disease to investigate how both disease-affected and healthy guts respond to these stimuli.
This work is done in the context of the Netherlands Organ-on-a-chip Initiative (NOCI), funded by NWO, and in collaboration with Emulate Inc., Boston, USA. More recently we have developed a liver-on-chip system as well that we will use to study the role of the gut-liver axis in drug metabolism and to study NAFLD/NASH biology.
We currently have an operational gut-on-a-chip system through our active collaboration with Emulate. We initially intend to use this platform to study celiac disease, an immune-mediated disease that affects the gut. Here we can utilize organ-on-a-chip to study how gluten peptides affect the immune system and microbiome and how the gut interacts with these factors in very high detail.
We have also generated a liver-on-a-chip to study the role of the intestine-liver axis in drug metabolism and their response to nutrients and drugs.
We dream of generating multiregional brains-on-a-chip as well, again by taking advantage of PBMCs stored in liquid nitrogen for 20,000 Lifelines participants. Since we have polygenic risk scores for each of these samples, we can use PBMCs from individuals strongly susceptible to brain disorders such as Alzheimer’s & Parkinson’s diseases, multiple sclerosis or ALS.
Connecting different organs-on-a-chip
By connecting these systems, we will be able to ascertain how the gut and liver interoperate and gain highly detailed insights into the metabolism of nutrients and drugs. We expect that the genetic makeup comprises a very strong factor in food and drug metabolism. Because we have PBMCs and polygenic risk scores for more than 20,000 participants, we can select those individuals with strongly increased or decreased risks for e.g. cardiometabolic disorders, which will enable us to study the effects on metabolism in unprecedented detail.
Leveraging existing multi-omics Lifelines cohorts
The PBMCs that have been stored in liquid nitrogen for more than 350 Lifelines Deep samples make it is possible to derive iPS cells that we can differentiate into a gut-on-a-chip. Additionally, as we have already generated a tremendous amount of multi-omics data on these samples, we can also integrate these in-vivo measurements with extremely well controlled organ-on-a-chip measurements. This will allow us to obtain extremely detailed insights into the interplay between the genome and environmental exposures.