A multi-institution collaboration – including researchers from Cornell and Weill Cornell Medicine – has created a human colon model that will be used to gather research on a tissue-engineering method that allows for forward genetics screening on human tissue.
Years ago, scientists developed the method of forward genetics – messages inserted into the genome of fruit flies to identify which genetic changes led to disease. The ability to perform the same type of study on human organs has, to date, been impossible until the model allowed for the research to commence.
The team created the model by first deleting cells from normal human colon tissue, while retaining most of the molecules to which the cells adhere. The tissue was then repopulated with cells obtained from colonoscopy patient samples and from commercial sources.
Then, using a technique developed in the 1990s for inserting specific sequences of DNA into a genome – called a “Sleeping Beauty” transposon – the group tracked the genetic changes that occurred inside the colon model, which were consistent with typical early stage colorectal cancer (CRC).
Further testing confirmed that this recellularized colon model is capable of replicating key features of CRC progression. The work identified 38 driver (disease-carrying) genes, including six that had not been previously implicated in CRC progression.
“You can’t really do experiments very well on human tissue,” said Michael Shuler, the Samuel B. Eckert professor of engineering. “So having a human system, which allows you to look at the genetics in the context of a controlled environment, is a fairly powerful technique.”
The millimeter-scale model provides major tissue-relevant elements, including complex structure, cell-matrix interactions and physiological co-location of multiple types of differentiated cells.
Shuler admitted that while it’s impossible to say the model provides an exact replica of CRC progression inside the body, “it gives you a human-based system to characterize some of the key steps in advance-stage colon cancer, and that is something that hasn’t been possible.”