The Power of Pairs: Why These Scientists Teamed Up to Study Neurodegenerative Diseases

As the old adage says, two heads are better than one.

Last year, as part of our Collaborative Pairs Pilot Projects RFA, we welcomed 30 pairs of researchers to our Neurodegeneration Challenge Network (NDCN). Collaborative Pairs is a unique grant program designed to catalyze new types of collaborations and encourage bold “out-of-the-box” ideas for tackling challenges related to the basic science of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS.

These pairs bring interdisciplinary and transformative approaches to studying these diseases, leveraging the power of collaboration to accelerate science. Many of these investigators are new to neurodegeneration research, and at least one researcher per pair is in their early- to mid-career. Additionally, the pilot project structure provides flexibility for researchers to take risks, test new ideas, and make adjustments to projects that will ultimately lead to more robust long-term research directions.

Building on complementary scientific expertise, some of these pairs have worked or studied together for years, while others met through neighboring labs, common interests, or even a shared love of nachos. Read on to hear from a few of these Collaborative Pairs on how they’re putting their heads together as they tackle projects to advance the study of neurodegenerative diseases.

Liam Holt and Hemali Phatnani

Liam Holt, Associate Professor in the Department of Biochemistry and Molecular Pharmacology at the NYU Grossman School of Medicine, has teamed up with Hemali Phatnani, Director of the Center for Genomics of Neurodegenerative Disease at the New York Genome Center (NYGC) and Assistant Professor of Neurological Sciences at Columbia University. Liam and Hemali are interested in studying how overcrowding inside of cells can contribute to neurodegeneration.

Left: A picture of a cell with the team’s nanoparticle probes inside. Image courtesy of Greg Brittingham. Right: An electron microscopy image of the crowded interior of the cell, illuminated by a nanoparticle probe. Image courtesy of Dimitry Tegunov.

What their project is focused on:

Nobody knows why neurodegeneration starts. Clearly something starts to go wrong as we age. If you could shrink down to the size of a molecule and walk around inside a neuron, you’d find yourself in an overwhelmingly crowded place, like being in the crowd at Times Square on New Year’s Eve. Inside neurons is an incredibly crowded, complex, bustling environment, so full of molecules and organelles that the system is close to jamming. We think that when we age, this crowd becomes even more dense, until the neuron begins to shut down. We are testing the idea that overcrowding inside the cell is a key factor that causes cellular components to start to stick together, leading to aggregate formation and disease onset.

This project is an exciting opportunity to look inside astrocytes and neurons in ways that have been impossible — until now — to find out just how crowded they are. Our partnership brings together diverse ways of thinking and complementary expertise to address important questions about cell biology through biophysical approaches and opening up new areas of research for each of our labs by tapping into the strengths of both labs. This kind of bridging of fields is crucial to make new discoveries.

How their collaboration began:

We met in Barbados at a conference two years ago. It’s funny that we had to go to Barbados to meet even though we worked only two miles apart in New York City — this really highlights how important networking can be! We were among the first to arrive, met at the picnic table, started talking and realized we wanted to approach the same scientific problem from different research directions. We had a lot of time to get to know each other and started to plan for collaborative research in the future.

Their advice for developing successful collaborations:

It’s crucial to be outward-facing and actively seek connections. This means taking risks and trusting people. We try to be very open with everything we’re doing, even though it can sometimes feel vulnerable to put yourself out there. It’s also very important to mentor trainees to have these same values and to be proactive. The only way that collaborations ultimately succeed is if trainees are empowered to work together.

Neurodegenerative disease is one of the most pressing healthcare needs that we face, and the problem is growing. The emotional and physical impacts of these diseases are crushing. We are excited to try and help. -Liam Holt, NYU Grossman School of Medicine

What they see as the key challenges in making progress on understanding neurodegenerative disease:

In this huge field, there is a lot of deep knowledge about specific diseases and mutations, but it is still very hard to synthesize knowledge. Part of this problem stems from a major lack of understanding about what initiates spontaneous disease, even though the vast majority of cases are sporadic and have no obvious underlying genetic origin. We hope to gain insights into how fundamental properties of cells may change as we age. We think this could be a missing link in understanding neurodegeneration.

Jennifer Phillips-Cremins and Kristen Brennand

Jennifer Phillip-Cremins, Associate Professor and Deans’ Faculty Fellow in the Departments of Genetics and Bioengineering at the University of Pennsylvania, and Kristen Brennand, faculty member at the Yale School of Medicine, are working together to study DNA organization and repeat instability in neurodegenerative disease.

Sterilization techniques are critical to stem cell culture and allow researchers to generate patient-specific neurons in the laboratory dish. Image courtesy of Kristen Brennand.

What their project is focused on:

There are over one million DNA repeat tracts in the human genome, or sections of DNA that repeat. The large majority seem to be stable and benign, whereas a small number undergo pathogenic expansion and contraction via mechanisms that are poorly understood and have been causally linked to diseases such as Huntington’s disease, amyotrophic lateral sclerosis (ALS), and Friedreich’s ataxia. A fundamental unresolved question is why disease-associated repeat expansions at some key genomic locations are susceptible to instability. Towards this, our work aims to resolve the causal link between DNA organization and repeat expansions in neurodegenerative disease, testing our hypothesis that disease repeat expansions are most severe in cell types where the integrity of higher-order DNA folding structures are compromised.

How their collaboration began:

After both being named New York Stem Cell Foundation Robertson Investigators, we met at the Investigator Retreat in Montauk, NY and bonded over our mutual love for science, running, genomics, and neurodegenerative disease. Chatting between scientific presentations, we also connected over our shared scientific interests and common experiences balancing new laboratories and young families. Over the last five years, we’ve been working on a strategy combining our expertise to tackle high-risk, high-reward projects in neurological disorders. Together, we combine principles from genome engineering, genomics, computational biology, and neuroscience to understand the onset and progression of neurological disorders with synaptic defects.

It is imperative that we unravel how disease risk factors interact within and between the diverse cell types populating the human body, towards improving diagnostics, predicting clinical trajectories, and identifying pathways that could serve as pre-symptomatic points of therapeutic intervention. -Kristen Brennand, Yale School of Medicine

What motivated them to work in the neurodegeneration field:

We are drawn to the neurodegeneration field because of the complexity and multi-faceted nature of the problems, and the great need for treatments to alleviate the suffering experienced by patients and their families. We do this work so that we might one day see common epigenetic patterns across several typically siloed disease states, thus revealing convergent points of therapeutic intervention. The variable penetrance of risk variants in brain disease represents a novel disease prevention strategy based upon biologically demonstrated “resilience.” For example, although APOE4/4 carriers have 15-fold increased risk for Alzheimer’s disease, one in 10 fail to develop symptoms. The compensatory molecular mechanisms involved represent strategies by which to prevent or delay symptom onset.

How they develop successful collaborations:

Our most successful collaborations are based not just on shared scientific interests, but also mutual responsibility and trust. We both feel that collaborative science is more innovative, more successful, and most importantly, more fun. Collaboration is important because it forces scientists out of their comfort zone into new research areas where new tools and knowledge can bring a fresh perspective to the problem. In this case, we’re both beyond thrilled to undertake this science together. It is a privilege to work with and learn from each other.

Melissa E. Murray and Wilfried Rossoll

Melissa E. Murray and Wilfried Rossoll, both faculty at the Mayo Clinic Florida, are working to develop a next generation approach to neuropathology, the study of diseases of the nervous system tissue.

Left: Red and green fluorescence-labeled proteins clump together into toxic insoluble aggregates in a cellular model of neurodegenerative diseases. Image courtesy of Bilal Khalil of the Rossoll lab at Mayo Clinic Florida. Right: Light-induced assembly of a red fluorescent protein into abnormal fibrils (cyan), often found in the brains of patients with dementia. Image courtesy of Jannifer Lee, Rossoll lab, Mayo Clinic Florida.

What their project is focused on:

A common feature of neurodegenerative diseases is the accumulation of specific proteins that clump together to form harmful aggregates in the brain. We are working to develop techniques that will enable us to modernize our understanding of brain diseases under the microscope.

Our project seeks to develop new tools that allow us to establish detailed molecular profiles of neuropathologic aggregates across neurodegenerative diseases, and combine them with advanced digital pathology, with the goal of identifying common disease pathways and modifiers as future therapeutic targets. To identify the aggregated proteins, specific markers are used to highlight brain changes that have contributed to the death of a patient. With our work, we hope to devise techniques to identify what features of aggregated proteins are common and unique across brain diseases. Using these novel experimental tools, we expect to identify proteins that regulate disease onset and progression, providing us with potential new targets for therapy development, and ultimately towards our goal of enhancing neuropathologic evaluation of human brain diseases.

How their collaboration began:

It began over our shared love of coffee and fresh air. We are colleagues in the Neuroscience Department at the Mayo Clinic Florida. Wilfried is a cell biologist who was recruited by the Neuroscience Department in 2017 to establish the Neurobiology of Neurodegenerative Diseases Lab. Melissa is a neuropathologist who was promoted as an internal candidate to an independent faculty position in 2019 to establish the Translational Neuropathology Lab. The CZI NDCN Collaborative Pairs program is our first formal collaboration as a molecular and cell biologist together with a neuropathologist.

Collaboration is like putting on the right set of glasses that enables you to see the world again with the complement of another individual’s set of expertise. -Melissa E. Murray, Mayo Clinic Florida

What they see as the key challenges in making progress on understanding neurodegenerative disease:

Among the numerous challenges to overcome is the sporadic nature and late onset of most neurodegenerative diseases in humans, which makes it difficult to faithfully replicate their phenotypes in cellular and animal models. For this reason, we see it as an imperative to learn from human patients as much as we can.

What motivated them to work in the neurodegeneration field:

We became interested in cell biology to discover what keeps our cells alive. Among all cells, neurons have the longest life and the biggest challenges, especially to sustain their high energy demand. If we figure out the pathways that keep neurons alive, then we will be able to prevent neuronal degeneration. Our work is motivated by the scientific challenge of solving fundamental questions about the disease process of neurodegenerative disorders, and by the tremendous impact that these devastating disorders have on patients, their families, and society.

Gulcin Pekkurnaz and Marc Hammarlund

Gulcin Pekkurnaz, Assistant Professor of Neurobiology at the University of California, San Diego, and Marc Hammarlund, professor of genetics and neuroscience at Yale University, are studying the pathways governing energy balance in healthy neurons.

Left: Complex mitochondrial network in a neuronal soma. Image courtesy of Gulcin Pekkurnaz. Right: Gulcin Pekkurnaz in the lab. Image courtesy of Gulcin Pekkurnaz.

What their project is focused on:

Neurodegeneration happens when mitochondria fail. Our goal is to understand the molecular pathways leading to this failure, in order to identify key points where neurodegeneration might be blocked. Studying neuronal metabolism is very much like opening Pandora’s box: It involves hundreds of interconnected reactions in elaborate neuronal architectures and rapid energy conversations.

Unlike other projects in our labs, this project focuses on in vivo cell-biological cross-species studies. We think such studies have the best potential to identify mechanisms that function outside the laboratory in human health and disease.

How their collaboration began:

We hadn’t worked together before this project. We first met at the HHMI Janelia, ‘Cell Biology of Neurons and Circuits II’ conference in 2019 and ended up having an extensive scientific discussion that led to sharing unpublished data and manuscripts. In turn, these discussions led to the idea of this collaboration. In the future, we will also spend two weeks together each July at the Marine Biological Laboratory Neurobiology course, where Gulcin is a course faculty and Marc is a co-director.

What tool or resource would make your lab’s research easier:

Our project heavily relies on microscopy and imaging tools to study the link between mitochondria, metabolism, and neurodegeneration. While we have ImageJ-based tools to analyze mitochondrial trafficking, neuronal morphology, and genetically encoded metabolism sensor data, we would like to utilize more robust computational tools. We’re especially interested in continuing to work closely with CZI on this.

What they see as the key challenges in making progress on understanding neurodegenerative disease:

One big issue is that neurodegeneration is an endpoint, and there are lots of different paths that can lead there. We hope that by focusing on endogenous mechanisms of homeostasis, we can identify mechanisms that are relevant across multiple paths to neurodegeneration.

I think about everything I do as a collaboration. This always includes the amazing people in my lab, and usually also involves working with people in other labs. The more we work together, the faster and deeper we can go. -Marc Hammarlund, Yale University

Learn more about the Neurodegeneration Challenge Network.

Supporting the science and technology that will make it possible to cure, prevent, or manage all diseases by the end of the century.