2025 Gilfillan Lecture: "Beyond the fold: How disordered proteins control movement, viruses and gene expression"

Barbar’s journey — from a young girl navigating a war-torn country to leading a university department — is a testament to the power of resilience and curiosity.

Barbar grew up in Beirut, Lebanon, in a family that prioritized science and mathematics. Though her initial pursuit of science was driven by aptitude rather than passion, she eventually found her calling. Her journey into biochemistry began in Lebanon, where she earned her undergraduate degree in chemistry at the American University of Beirut amid civil unrest.

A pivotal moment came when conflict in her homeland disrupted her academic opportunities. During this time, tragedy struck her family when her grandfather was killed by shrapnel during the Lebanese Civil War. This devastating loss, coupled with the ongoing violence, motivated her to move to the United States to continue her education.

It was during her postdoctoral work that Barbar fell in love with proteins. “I found a sense of belonging,” she says, describing the thrill of observing protein structures at the atomic level. “I was itching to see what comes next.”

Prior to the late 1980s and early 1990s, the scientific community thought of unfolded proteins as an anomaly – something that only happened in a lab. In the early 2000’s around the same time Barbar was starting her first laboratory, the discovery came that some proteins never fold, and they were meant to stay that way. This opened a tsunami of questions: If they don’t have a structure, what do they do and why?

“In the old days, if proteins were unfolded, you just threw them away because ‘what can I do with them?’ Because structure determines function, that was the old way of thinking,” Barbar said. “I was at the beginning of all of this and it was a beautiful time because I spent my postdoc years developing methods to work on partially disordered proteins and therefore had the skills to jump into this field.”

Intrinsically disordered proteins (IDPs), as they would come to be known, are a subset of proteins that, unlike traditional proteins, do not fold into a stable three-dimensional structure. Instead, they remain flexible and dynamic, enabling them to perform unique functions within cells. This lack of structure allows IDPs to act as molecular switches, regulators and adaptors, playing critical roles in processes like cell signaling, gene regulation and protein assembly.

“Nobody thought they were important. But then from our work, we showed that those other pieces that we thought were disposable, those are what tell the protein how to do what we call regulation,” she said.

Regulation is like a light switch. For example, if you have a protein that has a tail, that tail can cover its active site, preventing it from functioning. When the right signal comes along, the tail moves, activating the protein.

Her research demonstrates that their flexibility is not a limitation but an advantage — allowing IDPs to interact with multiple partners and regulate complex cellular systems with precision.

A protein with a rigid shape has a fixed number of binding sites, while IDPs are open and flexible, meaning they offer more binding opportunities.

Barbar’s research has shed light on the dynamic nature of IDPs and their roles in large molecular machines such as the dynein motor complex. This complex, essential for intracellular transport, relies on IDPs for assembly and regulation. Her lab’s innovative use of nuclear magnetic resonance spectroscopy has made it possible to study large, disordered proteins that were once considered too challenging to analyze.

By uncovering how IDPs regulate protein-protein interactions, Barbar's research has potential applications in designing new therapeutics for diseases driven by protein misregulation.

Exploration of the dynein motor complex was one of the first projects her laboratory undertook. While she was studying the dynamics of proteins, another scientist in the same building was working on the dynein protein. Understanding dynein requires understanding cellular movement. Imagine the different parts of a cell, like the nucleus and edges. It’s important to be able to move material inside the cell, and sometimes that movement happens by diffusing. Diffusing is similar to watching a drop of ink diffuse across a surface. However, diffusion can be slow so it isn’t always the best option.

The next option for movement in a cell requires motors, as the name dynein motor complex implies. These proteins move along train tracks in the cell and carry materials from one part of the cell to another. Although Barbar’s lab wasn’t interested in how that motion happens, they were interested in how multiple proteins came together to form a motor and then were able to carry materials.

“All of this requires so many steps, and something has to direct the process. Again, this is where the order of proteins comes in and the act of regulation — something directing when it’s time to deposit and then move again,” she said. “The complex is made up of proteins of many different sizes. They have to come together and that’s not an easy thing.”

The dynein motor complex is one of the largest molecular motors in a cell. For a size comparison, the dynein motor complex is 35 million times heavier than ethanol and 100 times larger. Dynein plays a key role in cell division, immune response and even neuronal function, meaning her insights could impact research on developmental disorders, neurodegenerative diseases and immune system deficiencies.

Barbar is primarily a nuclear magnetic resonance spectroscopist. This powerful technique is used to study the structure of molecules by measuring how their atoms interact with magnetic fields and radio waves. It provides detailed information about the positions and connections of atoms in a molecule, helping scientists understand how it behaves and functions. NMR is the only technique that can analyze disordered proteins, and traditionally, it’s used for small proteins.

“When we expanded to look at bigger proteins, we learned that the NMR can actually work. That is what makes our lab unique — that we can look at these large pieces because they are disordered. It’s a different way of looking at proteins than what other people have done.”

Her lab has made key insights into the cytoplasmic dynein motor complex, a specific type of dynein, revealing how its intermediate chain interacts with regulatory proteins to control intracellular transport.

She has also uncovered the function of the LC8 protein as a central hub that stabilizes and organizes multiple protein interactions, affecting cellular processes such as gene regulation and virus-host interactions. These contributions are crucial because they provide a molecular framework for understanding how cells transport essential cargo, maintain structural integrity, and adapt to changing environments. This breakthrough redefines LC8 as a master regulator, revealing how IDPs drive essential cellular functions – insights that could revolutionize disease research and treatment.

Barbar has never been one to accept obstacles or give up. The drive to complete her education and make a difference led her to leave her beloved home, forging a path that ultimately brought her to leadership in a rigorous university department.

And her relentless curiosity compelled her to explore proteins once dismissed as biological junk. She has transformed what was once considered scientific waste into a key to life’s inner workings. Her research has reshaped our understanding of these proteins, proving their critical role in cellular function. By demonstrating how IDPs regulate complex molecular systems—from intracellular transport to gene expression—she has challenged long-held assumptions and changed the way scientists think about protein structure and function. Sometimes, questioning the status quo makes all the difference.