Major collaboration creates cellular atlas of COVID-19 pathology
Scientists from several hospitals and research centers have shown what goes on in the individual cells of patients who have died from COVID-19. In a study published in Nature, the researchers describe how infected cells from several organs exhibited a range of molecular and genomic changes. They also saw signs of multiple failed attempts by the lungs to repair themselves in response to respiratory failure, which is the leading cause of death in patients with COVID-19.
“You really feel the tragedy of the disease when you see this result,” said Aviv Regev, lead co-author of the study and senior institute member at the Broad Institute at MIT and Harvard when the study began. . “The lung is trying everything that is available to it, and it still cannot repair itself. It was a very moving study. We are grateful to the patients and families who have agreed to donate tissue for COVID-19 research to help advance understanding of this pest. disease.”
Researchers studied tissue obtained from autopsies of 17 people who succumbed to COVID-19 and received treatment at Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital and Massachusetts General Hospital.
The team studied how the SARS-CoV-2 virus interferes with the function of cells and their genetic programs. They used single-cell RNA sequencing data from tissue samples taken from 11 organ systems – including the lungs, heart, liver and kidneys – to construct a complete “cell atlas” of hundreds. thousands of single cells showing how COVID-19 can lead to organ failure and death.
“We knew people were dying from pneumonia and extra-pulmonary complications related to COVID,” said Alexandra-Chloé Villani, associate fellow at Broad, principal investigator at Mass General, assistant professor of medicine at Harvard Medical School, and co. – main author of the study. “Prior to this study, we had limited knowledge of the cellular and molecular mechanisms involved in the disappearance of a patient.”
The study details the results of a collaboration of researchers from the Broad Institute, Mass General, the Ragon Institute of MGH, MIT and Harvard, MIT, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Columbia University Irving Medical Center and other institutions. A team led by Columbia collaborators co-authored a complementary study which is also published in Nature.
The team’s cell atlas is freely and openly available for other scientists to explore. They also created a biobank of 420 samples from the autopsy samples that can be used for further studies on COVID-19. “We have created a foundational resource that other researchers can use in the future to ask specific questions,” said Orit Rozenblatt-Rosen, co-lead author and scientist at the institute and scientific director of the Observatory of Klarman cells at Broad when the study began. . “Hopefully our findings will help people find better treatments for COVID-19.”
New techniques for a new virus
To learn more about the cellular mechanisms underlying organ failure caused by COVID-19, the researchers knew they needed to study the organs themselves. For that, they would need autopsy samples.
Working with autopsy samples is difficult under normal circumstances. To process samples that may carry a new, highly contagious pathogen, researchers have developed novel tissue collection and processing protocols that are compatible with the requirements of a biosafety level 3 laboratory.
“We wanted to make sure that we could learn and share as much as humanly possible to help prevent future deaths, while prioritizing the safety and well-being of everyone involved. This was no small feat, given the restrictions related to COVID and all the uncertainties surrounding it. It was amazing to see dozens of scientists and healthcare professionals from several institutes coming together in a collaborative partnership to carefully design and coordinate our experimental and computational efforts, ”said Alex K. Shalek, member of the institute and lead co-author, who is also a Fellow of the Ragon Institute, and Associate Professor of Chemistry, Senior Fellow of the Institute for Medical Engineering and Science, and Extramural Fellow of the Koch Institute for Integrative Cancer Research at MIT .
The team then profiled the RNA of individual cells and developed new methods to analyze and annotate the large amounts of sequence data. They compared the gene expression signatures of different cells: cells damaged by COVID-19 and uninfected cells from patients with COVID-19, as well as cells from patients with other diseases and individuals in healthy.
Devastation in the lungs
The most comprehensive series of discoveries came from the lungs. Scientists were amazed at the extent of the changes in the genetic programs they found there. “The virus takes its toll in the lungs and we see it in the cells,” Regev said.
One of the main causes of lung damage in COVID-19 is the destruction of AT1 cells, which allow respiration and gas transfer. Scientists found that when AT1 cells died, related lung cells called AT2 attempted to convert into AT1 cells through a process called transdifferentiation. But that attempt stopped halfway, leaving the cells in an intermediate state often seen in patients with other lung diseases such as pulmonary fibrosis.
In a latest attempt at self-repair, the lungs tried to turn cells higher up in the airways, called basal-intrapulmonary-type progenitor cells, into AT1 cells. This attempt at transdifferentiation had previously only been observed in mouse models.
The results suggest that lung failure in patients was caused by the inability of lung cells to overcome damage from the virus as the cells tried to regenerate.
Change of program
The article also describes how the virus affects other tissues besides the lungs. A surprising finding was that while the heart suffered significant damage and showed evidence of altered genetic programs in many different cell types, there was very little viral RNA in the heart tissue itself. “Whether this means the virus has already been cleared or the heart has been collateral damaged is a further area of research,” Regev said.
The researchers also looked at 27 different genes that previous genome-wide association studies had linked to severe COVID-19. They focused on a handful that were highly expressed in key cell types in the new study, particularly those in infected lungs. This finding helps refine the list of potential genetic factors for severe disease and highlights the cell types that may be most relevant in severe COVID-19.
The team now plans to complete the analysis of other autopsied tissues, such as the brain, spleen and trachea, to paint a more complete picture of the pathology of COVID-19 and provide a resource for future studies.
Aviv Regev is now Executive Vice President, Genentech Research and Early Development.
Orit Rozenblatt-Rosen is now Executive Director and Head of Cell and Tissue Genomics at Genentech.
About the Broad Institute of MIT and Harvard
The Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe the molecular components of life and their connections; discover the molecular basis of the main human diseases; develop new effective diagnostic and therapeutic approaches; and disseminate findings, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard, Harvard Affiliated Hospitals, and visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff, and students from all of MIT’s biomedical research communities and Harvard and beyond, with collaborations spanning over 100 private and public institutions in more than 40 countries around the world. For more information on the Broad Institute, visit http: // www.