Extramural basic research at the Mount Sinai School of Medicine, funded by the U.S. Army Research Laboratory – Army Research Office (ARL-ARO), has led to discoveries of the biochemical mechanisms for viral growth and of an unprecedented method that may inhibit viral replication.
These fundamental discoveries may enable the design of new antiviral therapies to rapidly combat new viral strains by providing a kind of adaptive immunity to the soldier and civilian.
This research is led by Professor Benjamin R. tenOever, who was selected for ARL-ARO funding early in his career.
Scientists within the ARL-ARO Life Sciences Division recognized tenOever’s innovative research ideas and nominated him for the prestigious Presidential Early Career Award for Scientists and Engineers (PECASE).
In 2009, the White House announced his selection for this highly competitive award, listing him as one of a small group of “young scientists…whose early accomplishments show the greatest promise for strengthening America’s leadership in science and technology.”
tenOever and his team study how cells respond to viral infection.
In 2003, while a graduate student, he was one of the first to discover a unique series of signaling cascades through which cells detect and respond to invading viruses. [tenOever et al., Science, 2003; tenOever et al., Science, 2007]
Once a virus enters a human cell, it begins reprogramming the cell to replicate the virus’ structure. Most viruses encode their genes using RNA. These viruses release their RNA genes into the cell during the infection process.
Pathogens and host organisms are engaged in a type of genetic arms race, with members of each side employing new attacks and counter-defenses in an attempt to win the battle for survival.
Cells use a variety of methods to resist viral infection. When human cells detect an invading virus, a series of cellular “alarms” ensue, aimed at stopping the infection.
This protein-based defense strategy includes shutting down many essential functions of the cell that are needed by the virus.
While human cells use proteins as the chief defense against viruses, they also encode short strands of molecules called “small RNAs” or “microRNAs.”
These microRNAs are used to control the cell’s overall health.
The tenOever lab specializes in exploiting the microRNA pathway to manipulate viruses independently from the strategy typically used for fighting these pathogens.
With ARL-ARO funding through the PECASE award, tenOever discovered that the natural microRNA pathway could be harnessed to study how a pathogen responds to specific, controlled changes, by introducing small RNA sequences that interact directly with a pathogen’s genes.
This discovery opened the door to subsequent studies in which tenOever demonstrated methods to deliver synthetic small RNAs to specific types of cells. [Shapiro, et al., 2010; Varble, et al., 2010, 2013; Langlios, et al., 2012a, 2012b, 2013; Chua, et al., 2013]
These small RNAs are harmless to humans, but provide a significant resistance to viral growth, and may allow a human’s natural immune system to eliminate an infection before significant symptoms develop.
ARL-ARO selected tenOever for a Single Investigator award 2013, to use this new approach to map a type of genetic and molecular mechanism that cells use to combat viruses.
In the long term, this research may be the key to winning an important battle in the genetic arms race with pathogens.
This research has great promise for use by the soldier and civilian alike, as it is likely the beginning of a new future for the antiviral arsenal.
These successes highlight the unique role of ARL-ARO in driving research in directions relevant to the Army.
While the results of these studies have already attracted the attention of other funding agencies and industry, the groundwork for these discoveries was laid by ARL-ARO investment in high-risk, fundamental research ideas that were too preliminary for funding elsewhere.
For example, ARL-ARO brought tenOever’s discoveries to the attention of the Defense Advanced Research Projects Agency (DARPA).
DARPA recognized the potential of tenOever’s published findings, and is now funding his laboratory to pursue future antiviral therapies, thereby building on fundamental discoveries made possible through ARL-ARO basic research funding.
However, several key challenges remain before these methods can be tested in the field.
Researchers need to determine whether these discoveries are compatible for use in other organisms and adaptable for different types of viruses.
The safety and effectiveness of these methods must also be demonstrated through rigorous laboratory and clinical studies.
Scientists at the U.S. Army Medical Research and Materiel Command (MRMC) are also following tenOever’s research, and are also interested in transitioning his discoveries to explore new methods to protect the soldier.
Dr. Marti Jett, chief scientist and director of Integrative Systems Biology at MRMC, stated that “this discovery appears to be quite remarkable; I envision many medical applications that will complement ongoing efforts at MRMC,” further highlighting the potential long-term opportunities this research may provide for the Army.
By Kelby Kizer, PhD
U.S. Army Research Laboratory – Army Research Office
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