With new Warren Alpert Foundation award, U-M researcher hopes to define the ‘RNA alphabet’

Vivian Cheung, M.D.

University of Michigan faculty member Vivian Cheung, M.D., is launching an international project to identify the full range of RNA building blocks inside human cells.

The effort, supported by a $2.3 million grant from The Warren Alpert Foundation, aims to lay the groundwork for a comprehensive “human RNome” project, similar to the Human Genome Project completed in 2003.

The Human Genome Project mapped the DNA in human cells by determining the order of the four bases that form the building blocks of DNA (adenine, cytosine, guanine, and thymine). The result was a genetic code, the instructions for operation embedded inside each human cell. Scientists are now pushing for a second sequencing project to map the RNA in human cells, and the idea is gaining momentum at the national level

“Particularly in the last three years, in the face of a global pandemic caused by an RNA virus, it has become extremely clear that we need a way to accurately sequence RNA,” explains Cheung, a professor of pediatrics and genetics in the U-M medical school. “To do that, we first need to identify the actual building blocks that comprise the sequence; but right now, we don’t even know what all the building blocks are.”

In order to make better vaccines and treatments, not only against RNA viruses, but to address a whole host of human disorders, we need to understand the human RNome. This project will move us closer to that goal

David Hirsch, Board Chair, The Warren Alpert Foundation

To produce the proteins that keep all cells — and organisms — functioning, DNA is first transcribed into RNA, and then RNA is translated into the appropriate type and quantity of proteins. 

“Along with DNA, the genetic code, RNA as the regulatory code provides cells with instructions to handle the enormous number of needs within a body,” Cheung says. “RNA is very complex because it needs to supply the necessary regulation."

This extended information comes in the form of hundreds of chemical modifications to add to the basic building blocks of RNA (adenine, cytosine, guanine, and uracil), allowing precise regulation of cellular functions in response to the organism’s ever-changing needs.

“These chemical decorations are functionally part of the spelling of the RNAs, so each one has its own unique function and is part of the comprehensive RNA alphabet,” Cheung says. “That means we have the potential for hundreds of individual functional building blocks that need to be identified and defined.”

Her lab at the U-M Life Sciences Institute is now working with collaborators at the Massachusetts Institute of Technology, the University of Cincinnati and the Institute of Molecular Biology in Mainz, Germany, to do just that. 

With funding from The Warren Alpert Foundation, the researchers plan to first establish explicit protocols for extracting and preparing RNA for potential sequencing, and then use mass spectrometry to determine which components are in the RNA from different human cells.

The results, they hope, would establish the foundational data that complement a report being developed by the National Academies of Science, Engineering and Medicine to launch a full Human RNome Project, sequencing human RNA.

“The Warren Alpert Foundation is dedicated to improving human health, we know that RNA is going to be an essential component of the future of medicine,” says David Hirsch, the Board Chair. “In order to make better vaccines and treatments, not only against RNA viruses, but to address a whole host of human disorders, we need to understand the human RNome. This project will move us closer to that goal.”

In addition to Cheung, this work will be led by Peter Dedon, M.D., Ph.D., of MIT; Mark Helm, Ph.D. of Institute of Molecular Biology in Mainz, Germany; and Patrick Limbach, Ph.D., of the University of Cincinnati. 

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About The Warren Alpert Foundation

The mission of The Warren Alpert Foundation is to improve the health of the public through grants and programmatic activities progressing towards attaining or perfecting medical treatments or cures through basic research, translational and outcomes research as well as through health education.