MIT Researchers Develop “Organ-on-a-Chip” to Aid Drug Development

Dev Kapadia ’23

Figure 1:
A diagram of the process of developing an organ-on-a-chip. Because the cells must be able to behave like the target organ and grow on the chip, scientists take Induced Pluripotent (iPS) cells that can grow and differentiate into the organ that the scientists are aiming to replicate. Once these cells are grown, they are implanted onto the chip and manipulated by adding various substances.
Source: https://commons.wikimedia.org/wiki/File:Stemcell_and_organ_on_a_chip.jpg

With so many consumer products in today’s market, an emphasis for future development is to make future models larger or smaller, depending on general preferences. For instance, the screens of new television models are becoming increasingly large to provide the biggest and best picture for the viewer. Hardware chips, on the other hand, are being developed to pack even more memory and capability into smaller spaces. But even as these products change size, they still maintain or augment the functionality of the previous model. Can the same methods be applied to models used in biological laboratories, like those of human tissues and organs?

Biological engineers at MIT have created multitissue models on microfluidic chips that allow them to study how different organs interact with the immune system.1 Each of these chips are known as an “organ-on-a-chip.” Each chip has several small channels that connect at the ends. Each of these channels harbor living cells of a particular organ and can be manipulated by supplying fluid substances to the channels. These fluids can be various liquids with dissolved nutrients, proteins, and more to be supplied and to manipulate the cells.2

About twenty years ago, Dr. Linda Griffith started working on “organ-on-a-chip” technology, modeling the human liver on these microfluidic chips. Now, the Griffith laboratory has developed a chip so robust that it can model the interactions of up to ten organs at once. On one of these chips, one to two million cells of each of the ten tissue samples (liver, lung, gut, endometrium, brain, heart, pancreas, kidney, skin, and skeletal muscle) are placed on a singular chip with pumps to manipulate the liquid flow on the chip, simulating the circulation of blood, immune cells, and proteins throughout the body. Griffith notes that this technological capability is especially useful for drug development, as it allows researchers to observe the effect of drugs on organ systems, as well as interactions between those organs systems, without using animal subjects.3

In her most recent study, Griffith and MIT postdoc Dr. Martin Trapecar aimed to model the effects of inflammatory bowel disease (IBD), an illness that develops in up to eighty percent of people who have autoimmune liver diseases. The two researchers modeled the interactions between the colon and the liver and observed how the immune system, and T cells specifically, affected the diminished function of the organs.4

Griffith and Trapecar developed a single chip that held both healthy liver cells and colon cells taken from patients with ulcerative colitis, a type of IBD. When the tissues were connected, the inflammation associated with the ulcerative colitis gut tissue decreased. At the same time, certain genes the regulated immune activation expressed in both organs that regulated metabolism and immune function became more active. Given that inflammation decreased, the researchers decided to observe what would happen when they used T cells to provoke inflammation. They added two types of T cells: Th17 cells (to amplify inflammation) and CD4+ T regulatory cells (to suppress the immune responses). When the two cell types were added, characteristics associated with IBD and autoimmune liver diseases were observed in the system along with increased inflammation, showing that even when connected in a system, the healthy colon cells could not deter inflammation exhibited by the IBD affect cells if inflammation stimulators were introduced to the body.1

Lastly, researchers tested the effect of adding short-chain fatty acids (SCFAs). SCFAs metabolize undigested fiber and were previously determined to be beneficial to the body. For instance, SCFAs have been observed to increase ATP production from the food digestion and fermenting gastrointestinal fibers to increase energy intake.5 They have even been shown to reduce the symptoms of IBD, increase liver metabolism, and augment immune tolerance in the body.6,7 However, recent studies determined that they may actually cause harm by stimulating inflammation. Griffith and Trapecar found that for the cells on the chip taken from patients with ulcerative colitis, the SCFAs severely increased inflammation, but only after T cells were already added to the chip. The impetus for this study came from a different study conducted by Sarkis Mazmanian at Caltech. Mazmanian showed that germ-free mice developed Parkinson’s disease before mice that are in normal environmental conditions, which researchers believe to point to SCFAs produced by microbes causing the development of Parkinson’s. These germ-free conditions produce SCFAs in order to allow full inflammatory capabilities of the microbes.8 Building off of this study, Dr. Griffith’s lab is currently working to take the interconnected colon-liver organ system used in ulcerative colitis experiment to determine the relationship between SCFAs and Parkinson’s disease. The researchers are hopeful that their technology can help elucidate the mechanisms behind many other diseases, paving the way for the development of new drugs.1

References:

[1] Massachusetts Institute of Technology. (2020, March 18). Using ‘organs-on-a-chip’ to model complicated diseases: A new approach reveals how different tissues contribute to inflammatory diseases such as ulcerative colitis. ScienceDaily. Retrieved March 21, 2020 from www.sciencedaily.com/releases/2020/03/200318143758.htm

[2] Microfluidics and microfluidic devices: a review. (n.d.). Elveflow. Retrieved March 22, 2020, from https://www.elveflow.com/microfluidic-reviews/general-microfluidics/microfluidics-and-microfluidic-device-a-review/

[3] Trafton, A. & MIT News Office. (2018, March 14). “Body on a chip” could improve drug evaluation. MIT News. Retrieved March 26, 2020, from http://news.mit.edu/2018/body-chip-could-improve-drug-evaluation-0314

[4] Trapecar, M., Communal, C., Velazquez, J., Maass, C. A., Yu-Ja, H., Schneider, K., . . . Griffith, L. G. (2019). Gut-liver physiomimetics reveal paradoxical modulation of IBD-related inflammation by short-chain fatty acids. Cell Systems 10(3), 223-239. doi:http://dx.doi.org/10.1101/706812

[5] Leblanc, J. G., Chain, F., Martín, R., Bermúdez-Humarán, L. G., Courau, S., & Langella, P. (2017). Beneficial effects on host energy metabolism of short-chain fatty acids and vitamins produced by commensal and probiotic bacteria. Microbial Cell Factories16(1). doi: 10.1186/s12934-017-0691-z

[6] Koh, A., Vadder, F. D., Kovatcheva-Datchary, P., & Bäckhed, F. (2016). From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites. Cell165(6), 1332–1345. doi: 10.1016/j.cell.2016.05.041

[7] Chang, P. V., Hao, L., Offermanns, S., & Medzhitov, R. (2014). The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proceedings of the National Academy of Sciences111(6), 2247–2252. doi: 10.1073/pnas.1322269111

[8] Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., … Mazmanian, S. K. (2016). Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson’s Disease. Cell167(6), 1469–1480. doi: 10.1016/j.cell.2016.11.018

 

 

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