In Search of Hidden Gems: Data-Driven Discovery

A closer look

St. Jude structural biologists can see farther into cells than ever before. They use the world’s most advanced tools to reveal once unknown molecular structures. Those tools include X-ray crystallography, single-molecule imaging, mass spectroscopy and high-resolution nuclear magnetic resonance spectroscopy.

Now, Babu brings data science approaches to St. Jude, providing new insights into variations in molecular structures.

He and his colleagues have integrated information on protein structures with human genetics and transcriptomics data. They found multiple GPCR gene variants that give rise to slightly altered shapes of the same receptors — changing the nature of the signaling messages. The findings may explain why side effects occur with currently available targeted therapies that address only one variant. The findings may also explain why some drugs work well in cell models but fail in animal models — hence, never making their way to patients.

At St. Jude, Babu aims to understand how different families of GPCRs may play a role in pediatric cancer, because many GPCRs are key players in the immune system.

He is investigating a family of GPCRs called chemokine receptors. They regulate how immune cells travel to cancer cells and interact with them. Targeting chemokine receptors with drugs could help the immune system better identify and attack the cancer cells.

Diamonds and dependencies

“Initiatives such as the Pediatric Cancer Genome Project [led by James R. Downing, MD, president and CEO of St. Jude] have provided an unparalleled view of the landscape of where things have gone wrong with cancer,” Babu says.

St. Jude researchers are capturing these — and other — massive amounts of data and are making that data available to researchers across the world through the St. Jude Cloud.

“This presents unprecedented opportunities to discover mechanisms and events that lead to altered behavior at the molecular level, eventually paving the way to fix them,” Babu says.

That’s where big data science comes in. Babu and his team develop new methods to analyze and mine data from many sources, including DNA sequences, gene expression profiles, proteomics, protein structures and details about the shapes of compounds that could lead to drug candidates.

Virtual drug discovery

St. Jude researchers are using 3-D computer modeling techniques to screen billions of chemical compounds to see if one might lock into proteins of interest. Recent advances in computing power have made it possible to whittle that list to a manageable size.

“Once you know the shape of the molecule, you want to discover a compound that will bind and perturb its function. That compound will eventually become a drug,” Babu explains. “But the chemical space is vast. There are many different compounds, and we don’t know which one is going to be able to bind to it.

“We can’t do an experiment to test a billion compounds,” he continues. “How could we even test that many?”

That’s where, again, computers come in handy.

“At St. Jude, we have the technological expertise and computing power to do just that,” he says.

Babu is particularly interested in revealing the unique biological weak points in cancer cells that are not present in normal cells. These weaknesses are known as dependencies. His team strives to discover mechanisms involving previously unstudied GPCRs, also called orphan receptors, that are dependencies in pediatric cancers.

“We don’t know yet what messages many of these orphan receptors respond to,” Babu says. “We aim to identify which ones play important roles in cancer. For this, we use our analysis methods in combination with the thoughtfully set-up core facilities and other resources within St. Jude to investigate them further.”

Babu says he hopes his discoveries about dependent GPCRs can drive virtual screening efforts to reveal such compounds.

Data science approaches can also identify drugs already approved for other health conditions that affect the same dependencies cancer cells use to survive. That means it may be possible to repurpose drugs already approved for other health conditions to treat pediatric cancers driven by the same variants.