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3 Princeton faculty win ‘High-Risk, High-Reward’ grants for bacteria research

<p>Lobby of the Lewis-Sigler Institute. LSI photo by Dante Tisi.</p>

Lobby of the Lewis-Sigler Institute. LSI photo by Dante Tisi.

University Professors Coleen T. Murphy, Mohamed Abou Donia, and Zemer Gitai were recently named recipients of ‘High-Risk, High-Reward’ grants from the National Institutes of Health (NIH). 

Each received the NIH Director’s Transformative Research Award for their joint project, entitled “Small RNAs as Novel Modulators of Microbe-Host Interactions.” Murphy also received the NIH Director’s Pioneer Award, which “supports scientists with outstanding records of creativity” according to the award webpage, making her the only recipient this year to be given both grants. 

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The ‘High-Risk, High-Reward’ grants are designed to provide funding for projects that would typically struggle to receive grant money through traditional means due to the risks associated with conducting them. 

According to the NIH official press release, the program “catalyzes scientific discovery by supporting highly innovative research proposals that, due to their inherent risk, may struggle in the traditional peer-review process despite their transformative potential.” 

According to the release, those applying for the grants “are encouraged to think ‘outside the box’ and pursue trailblazing ideas in any area of research relevant to the NIH’s mission to advance knowledge and enhance health.”

Gitai expressed excitement in an email to The Daily Princetonian. 

“I am deeply appreciative of this award. This research represents a new direction for my lab and a new set of collaborations with two amazing other groups in the Murphy and Donia labs,” he wrote. 

He added, “It’s exciting work that would not be fundable by traditional mechanisms, so this is a fantastic opportunity.”

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Donia echoed this enthusiasm both for the funding and opportunity to collaborate with two other University labs in an email to the ‘Prince.’ “We are very grateful and excited to have received this grant, which will allow us to embark on a new research direction that we have never worked on before in collaboration with [these] two amazing research groups at Princeton,” he wrote.

Alongside echoing enthusiasm for the transformative research award, Murphy expressed gratitude for also receiving the Pioneer Award in an email to the ‘Prince.’

She wrote, “The Pioneer award will allow us to carry out a wide range of experiments that will help us better understand transgenerational inheritance, and it will also help support the training of students and postdocs.”

The professors’ joint project seeks to address two major problems at the center of current biology research: the prevalence of antibiotic resistance in pathogenic bacteria and the unknown ways in which bacteria communicate. 

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One molecule lay at the center of this project — small RNA (sRNA) — which is produced both by the bacteria found naturally in our bodies and invaders. The researchers recently found that model animal hosts can recognize and “read” these small pieces of genetic material that were originally produced by the bacteria.  

This phenomenon is known as sRNA-host signaling. The researchers hope to further characterize the scope and mechanisms by which these interactions take place. 

Historically, the field has focused on small molecules, such as antibiotics and signaling molecules that bacteria use to promote cellular processes and interactions with other bacteria, to deal with bacterial pathogens. Switching the conversation to sRNA, a nucleic acid, is a “high-risk” approach. 

“Host-pathogen interactions were traditionally thought to be dominated by small molecule and protein-based signaling mechanisms,” Gitai wrote. “In the past [my lab] discovered how bacteria can also use unconventional signals like a ‘sense of touch’ to detect that they are on or in a host.” 

“With the Murphy lab, we also helped show that hosts can determine which bacteria they encounter by [this] new RNA-based mechanism,” he continued.

Murphy’s lab observed the sRNA-host signaling in Caenorhabditis elegans (C. elegans), a microscopic worm that is commonly used as a model system in molecular biology research. In addition to finding that the worms can “read” the genetic information and use it to avoid pathogens, they found that C. elegans can transfer this learned information to both their progeny (in a mechanism known as vertical gene transfer) and to neighbors in proximity (which is called horizontal gene transfer). 

Murphy said that her lab “has uncovered several separate and surprising mechanisms that worms use to ‘read’ pathogen information and to share this information with their progeny and kin.”

According to Gitai, approaches that focus on RNA are of interest to the field. 

“[It] is particularly exciting because RNA-based mechanisms are programmable (similar to how mRNA-based vaccines could be quickly deployed for COVID-19),” he wrote. 

What does it mean to be ‘programmable’? Because RNAs are genetic material made up of sequences, scientists can design their approaches around these sequences. In the COVID messenger RNA (mRNA) vaccine, scientists were able to synthesize a piece of mRNA that encoded a key protein in the COVID-19 virion, i.e., they ‘programmed’ it. 

Each researcher specializes in a subset of molecular biology research, allowing them to provide unique insights as the project moves forward.  

Donia, an Associate Professor of Molecular Biology, focuses on the human microbiome and computational cell biology. His lab, which was established in 2014, uses a combination of metagenomic, biochemical, and computational approaches to research the influences of the human microbiome on health, and potential therapeutic approaches. 

“We are interested in understanding how microbes, and especially bacteria, that live in and on our bodies interact with our human cells, and the consequences of these interactions on our health and disease,” Donia explained in his email.

Gitai is the University’s Edwin Grant Conklin Professor of Biology, and is an expert on microbial pathogenesis and antibiotic development. His lab uses quantitative, molecular, and engineering-based approaches to ask questions about bacterial biology and understand antibiotic mechanisms. 

In his email, Gitai was able to summarize his research in a simple statement, writing that his lab “is interested in how bacteria interact with their environment.”

Murphy, a Professor of Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics, looks at behavior in C. elegans and genomics. Her lab has developed worm-based models to study aging. 

In her email, Murphy described her research in two parts.

“We are interested in how animals (in this case, C. elegans) can 1) identify pathogens and learn to avoid them, and 2) pass this information on to their progeny,” she wrote. 

According to Gitai, the end-goal of the project is to better understand the dynamics of bacteria-human interactions. This is where Donia’s expertise will come in. 

He wrote, “the hope is that by understanding this new type of RNA-mediated signaling between bacteria and hosts we can better understand and manipulate how harmful bacteria make us sick and how beneficial bacteria make us healthy (this last part will be led by the Donia lab).”

The two model organisms at the center of the project — bacteria and C. elegans — are invisible to the naked human eye. Yet, they play a significant role in molecular biology research today. 

All three researchers pointed to the usefulness of their choice model system in the context of biological research. 

“Because C. elegans shares many of its genes with us, there is not only the possibility that we will learn new and interesting biological phenomena, but also that there might be information we can use that could apply to humans,” Murphy wrote in her email.

In his email, Gitai described bacteria as “fascinating.” 

“As small cells that rapidly grow on their own, they are amazing yet relatively simple models for understanding the fundamental features of cellular life,” he wrote. 

Along with being model systems, bacteria have many applications to the real world, making them even more of an interest. 

“Bacteria have an enormous influence on the world, including our health and the environment,” Gitai wrote, “[L]earning how to manipulate bacteria can provide solutions to a staggering array of real-world challenges, from health to climate to hunger.”

Donia echoed this enthusiasm for the study of bacteria, and the importance of understanding how they interact with human health.  

“We are full of bacteria! Every exposed human surface, like the skin, the mouth, and the gastrointestinal and urogenital tracts is home to a diverse community of bacteria,” he wrote. 

He added, “These microbes don’t just live there idly, they have evolved important functions that do impact their host — us!” 

Zoya Amir Gauhar is a senior writer who often covers research and the sciences. She can be reached at zgauhar@princeton.edu. She enjoys combining her science background and interviewing abilities to learn more about the people behind the research.  

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