A team of researchers comprising of experts from the Massachusetts Institute of Technology (MIT), Harvard and the Massachusetts General Hospital (MGH) have drawn up detailed imagery of a disease infected colon in an attempt to better understand chronic Inflammatory bowel diseases.
The team took samples from the intestines of patients who had developed ulcerative colitis. The disease is chronic and more than 200000 cases are reported in the US each year.
The reason ulcerative colitis was selected is that diseases like it and Crohn’s are not fully understood by the experts and every patient has highly variable treatment courses. People having the same condition may have to be treated differently and with different drugs. The symptoms can vastly vary as well.
The tissues taken from the ‘infected’ intestinal walls were put up against those from a healthy intestine and mapping was done on more than 350000 individual cells. This practice was repeated on 30 different patients to increase the accuracy of the results.
The data obtained successfully identified changes in the composition of the cells and a subset of cells was identified that resisted repair attempts by drugs. A set of genes that made individuals more prone to contracting ulcerative colitis was also discovered. A detailed report on the findings from the research is published in the science journal Cell.
A senior member of the Broad Institute of MIT and Harvard Mr. Ramnik Xavier commented, “Having a map of the common molecular activity, and examining the cell-specific biology that is altered in disease, opens doors to new diagnostic and therapeutic hypotheses that we can now explore to ultimately improve patient health,”.
Mr. Ramnik Xavier also serves as a co-director of the Infectious Disease and Microbiome Program at Broad and director of the Center for Computational and Integrative Biology at the Massachusetts General Hospital.
The study is a rather significant one as the team had big names associated with it and it is the first time that we have come this close to the underlying mechanism of the inflammatory bowel diseases. Senior co-authors include Christopher Smillie, Moshe Biton, and José Ordovas-Montañes all of whom have co-authored numerous books on the subjects of human biology and cell-makeup.
This study is a part of an international collaboration between biologists, scientists, mathematicians, physicists and even software engineers which seek to map the cells of the human body in an attempt to develop an understanding of it. The project, known as the Human Cell Atlas project, is one of its kind and is striving to improve the disease treating conditions by understanding the cellular make-up and genes which they express.
Prominent figures like the director Crohn’s and Colitis Center Massachusetts General Hospital, Ashwin Ananthakrishnan and Aviv Regev, core institute member and director at Klarman Cell Observatory at Broad-MIT & Harvard were also on the panel of researchers. Mr. Aviv is also a professor of biology at MIT, and a principal investigator at the Howard Hughes Medical Institute.
Mr. Regev is the co-chairman of the Human Cell Atlas project. The data collected during the research is available on the Single-cell and DUOS portals of the Broad Institute.
In-depth analysis of the test subjects helped the researchers discover that over 50 types of cells in the body are immune.
The samples sourced from the healthy and affected individuals exhibited a huge contrast. the differences were evident in both their physical dimensions and their intercellular interactions. The samples sourced from the colon of patients who were suffering from ulcerative colitis had microfold cells which is a typical of the small intestine lining. Patients also had a special type of connective cell associated with the inflammation.
Perhaps the most iconic finding of the study was that the cells were communicating with each other and one could dictate the interaction with the other. The researchers concluded that the colon of patients who had contracted either the ulcerative colitis or the Crohn’s had colons which have developed some sort of a cellular network which can communicate and adapt.
Are patients developing resistance to drugs?
The team’s agenda included looking to the matter of patients not responding to treatment drugs. Mapping the gut helped a lot in the matter as the team gained important information regarding the suspected drug resistance mechanism in ulcerative colitis patients.
It was found that the anti-TNF (tumor necrosis factor) drug administered to patients helped reduce the inflammation and healed many tissues but around 30% of the patients started developing resistance to the drug over a period of time. Patients with inflammatory bowel diseases had high levels of tumor necrosis factor protein.
Prior studies helped with the findings as the genes associated with treatment resistance had already been identified. The problem at hand was identifying the cells in the colon region which expressed these genes. Using the data from the findings the researchers singled out the inflammation-associated fibroblasts as the possible culprit. Once the culprit was identified the cells that it interacted with to undermine the effect of the drugs. It seems that the fibroblasts respond to the Oncostatin M signaling molecule to bypass the TNF pathways and hence the drugs
The findings from this study could be used to help identify patients who are likely to develop drug resistance, Smillie said: “Patients with these resistance markers could be identified in advance and perhaps given another drug in conjunction with anti-TNF therapy to treat their disease, targeting these specific cells.”
New gene-expression information found in the study
By making the use of the newly formed cell atlas the researchers were not only able to identify the problematic cells they found out which cells express which genes and the possible role that they play in favor of or against the diseases. Previously it was unknown that the microfold-like cells in the colon of patients were expressing many genes associated with diseases of the gut. This piece of information is key in finding the best remedies for diseases like Crohn’s and Ulcerative colitis.
“Our analysis provides a framework for using single-cell analysis as a roadmap to new insights into human health, taking a plethora of individual genes and cells in complex tissue and distilling the key genes, pathways, cells, and interactions that underlie disease,” says Regev. “This was a major collaborative effort, from the clinical to the experimental and computational team members, and we hope that the analyses will pave the road to combining genetics and single-cell genomics to better understand complex diseases.”
The mapping of the body cells is a stepping stone which will pave way for future studies. The researchers on the team gave a much-needed insight into the gene expression of the problematic cells and the pathways used which will enable us to combat these complex diseases.