Sinha Receives $1 Million NIH Grant to Model Gene Regulation
Anyone who has been to a symphony knows that the beauty of the music depends on each player and section of the orchestra starting at the proper time, and then ending at the proper time. Only when everything occurs in the proper order and in sync does the musical piece make its statement.
All of this would be quite difficult without the work of the conductor who coordinates the piece, and signals musicians when to begin and when to stop.
For CS Professor Saurabh Sinha, the development of life works much the same. As an organism develops, the genes found within the DNA begin turning on and off in a particular order to have the organism develop in a particular way. “There’s a very precise coordination of the timing and the location of genes turning on and off, like a massive symphony that’s coordinated with exquisite detail,” he said. “It’s been an open question how this orchestration of thousands of genes happens in a precise way, and in the same way from one organism to another.”
To help answer this open question, Sinha—who is a Donald Biggar Willett Scholar—recently received a $1 million grant from the National Institutes of Health to begin a four-year project titled "Quantitative Modeling of Sequence-to-Expression Relationship." The focus of the project will be gene regulation—understanding how genes are turned on or off in a particular cell at specific times as an organism develops. “That process of development is a huge mystery,” said Sinha. “We have a rather poor understanding of how that same DNA in one cell can give birth to all the kinds of cells we have in our bodies. One cell with one copy of DNA from each parent is giving rise to a body.”
In a sense, Sinha is interested in uncovering the conductor in the symphony of life. What is the process that oversees ad coordinates the implementation of particular genes at specific times?
DNA is made up of a series of nucleobases: adenine (A), cytosine (C), guanine (G), and thymine (T). With just these four bases set in a particular sequence with DNA, an individual organism is able to develop fully from a single cell. As Sinha explained, “We know the alphabet [of DNA], which is A, C, G, and T, but a lot of complex stuff is written with this alphabet, and we do not know that language.”
Some parts of DNA are understood: the genes. Studies of the genomes have helped map out these portions of the DNA. So it is understood that particular parts of DNA (the genes) have impact on certain areas of development, but “the rest of the DNA, which comprises a whopping ninety-eight percent of the human DNA, is not genes,” said Sinha. “In fact, a lot of it is dedicated to controlling the activity of genes.”
And how that 98% of the DNA controls the other 2% remains a mystery—a mystery that Sinha will explore. He hopes to reveal the actions of the conductor of this symphony of gene regulation.
Sinha’s project will use computational algorithms to model the available data on DNA. The data for this project come from genetic information on fruit flies provided in part by Professor Stas Shvartsman, Sinha’s collaborator at Princeton University. Analysis of these data will lead Sinha to be able to model how changes to a particular genomic sequence may affect the gene regulation process.
Sinha explained: “We use methods that are based on biophysical principles. Principles of how different molecules interact with each other. We encode those ideas into algorithms that can run fast and process large amounts of sequences. Then we use these tools to see if they can explain experimentally collected data.”
After developing the models, Sinha will better be able to predict what effect a mutation—even the smallest mutations—may have on an organism’s development. “Our model could be able to predict the effects of even a single nucleotide mutation,” he said.
The knowledge that can be gained from research like that being undertaken by Sinha could lead to the development of precision medicine. There are many instances in which different medications for a similar disorder will affect patients differently. Precision medicine would enable doctors to examine a patient’s genome and determine more accurately which particular regimen would be the most beneficial for a particular patient.
Though the potential health benefits are exciting, and though these are the basis for the NIH funding his project, Sinha is just as excited about the basic science questions that his research could answer. “To me what’s equally important—as important as the health applications in precision medicine—is the promise of these methods to answer fundamental, unsolved problems of biology,” he said. “The question of how an organism develops—people have been going at that for a hundred years now.”