Supporting Bold and Transformative Ideas in Neurodegeneration

Announcing Collaborative Pairs Pilot Projects, Our Newest Neurodegeneration Challenge Network Grantees

The Chan Zuckerberg Initiative believes that the strongest scientific teams incorporate a wide range of lived experiences that guide them to the most important unsolved problems, and that the greatest advances in science come from interdisciplinary, collaborative work across disciplines. We launched the CZI Neurodegeneration Challenge Network (NDCN) in 2018 with the vision of building a new type of interdisciplinary collaborative research community, one that brings together biologists, computational scientists, engineers, and physicians from across broad research areas who are motivated by collaboration and open science to solve neurodegeneration.

Neurodegeneration is one of society’s most critical issues — millions of people worldwide suffer from diseases like Alzheimer’s, Parkinson’s, ALS, multiple sclerosis, Huntington’s, and many others. Over the next 30 years, the rates of these diseases are projected to grow. Moreover, there are few effective treatments or cures for neurodegenerative diseases, and in most cases, we still don’t fully understand the underlying causes or biology.

Human neurons, shown here, can now be reliably generated from stem cells and are used by the Ward lab to model neurodegenerative diseases in a dish. Photo provided by Michael Ward, National Institutes of Health.

Our vision and aspirations for the Neurodegeneration Challenge Network extend beyond neurodegeneration — we envision the Challenge Network as a community with the potential to be more than the sum of its parts and a model for how open science and collaboration can accelerate science and lead to disease treatments. Since December 2018, the first cohort of NDCN scientists — 26 teams across 48 labs, working on diverse diseases and deploying a wide range of methodologies and strategies — have come together to manifest that vision.

We’re excited to now launch the next phase of NDCN with the Collaborative Pairs Pilot Project teams. In designing this phase, we looked to build on the established community and values as well as innovate with our grantmaking. We are funding 18-month grants for 30 pairs of collaborating investigators to explore innovative approaches that address cross-cutting questions related to neurodegenerative diseases. These pilot projects will be incubated for the initial pilot phase of the RFA competition, and successful projects will be eligible to apply for additional grant awards of $1.6 million over four years.

Staining of lipid storage organelles in human astrocyte cells. Photo provided by Rik van der Kant, Amsterdam UMC.

Collaborations can take many forms — from teams of two to large consortia. While we tend to think about creativity coming from the singular lone genius, looking more closely, it’s often creative duos and partnerships that fuel the engines of innovation.

We picked pairs for this grant program because they are a nimble and personal way of working. Historically, collaborative teams of two have had an outsized impact on science. Consider the Nobel Prize-winning work of Marie and Pierre Curie for their work on radioactivity, Hubel and Wiesel for their work on visual perception, and Brown and Goldstein for the discovery of cholesterol metabolism. One plus one can often add up to much more than just two.

“Two are better than one for dreaming up theories and constructing models. For with two minds working on a problem, ideas fly thicker and faster. They are bounced from partner to partner. They are grafted onto each other, like branches on a tree. And in the process, illusions are sooner nipped in the bud.”

— Francois Jacob commenting on being part of a Nobel Prize-winning duo with Jacques Monod that originated the field of gene regulation.

We created the Collaborative Pairs Pilot Projects grant program as a way to catalyze new types of collaborations and encourage bold risk-taking, “out-of-the-box” ideas for tackling challenges related to the basic science of neurodegenerative diseases. The application process was designed to encourage new teams and new ideas — no preliminary data, previous work together, or even prior experience in neurodegeneration research was required to apply. We looked for talent, expertise, and great ideas. We’re excited that this group working on 30 pilot projects includes cell biologists, RNA biologists, neuroscientists, immunologists, cancer researchers, computer scientists, and even a plant biologist. Many of these investigators are new to neurodegeneration research.

Collaborative Pairs also builds on CZI’s commitment to support early-career researchers. Each pair was required to include at least one early- or mid-career investigator. Of the 30 selected teams, 87 percent of collaborations feature an early-career researcher, and six of the 30 teams are duos of two early-career researchers. Thirty-eight percent of the investigators self-identified as female. Physicians are a critical part of NDCN, grounding the Network in key clinical issues and what is important to patients. The 30 teams include 13 MDs or MD-PhDs.

This grant program aims to also continue to target work that addresses neurodegenerative diseases in a holistic way — recognizing that while there are distinctions between these diseases, there are also common biologies and mechanisms across disease categories. We encourage investigators to look for ways to drive the development of transformative treatments and cures that capitalize on shared mechanisms and approaches.

Researchers in the laboratory of Dr. Timothy Miller, David Clayson Professor of Neurology at Washington University in St. Louis, study how modifying gene products can protect against neurodegeneration. Photo provided by Timothy Miller.

Through the support, mentoring and collaborative interactions of the NDCN, we aim to empower these teams and these early- and mid-career investigators to pursue bold ideas and to take research risks. We’re excited to see how these projects accelerate the science of neurodegeneration — and ultimately, the path to treatments. Read more about the 30 selected projects.

Projects funded through the Collaborative Pairs RFA

• 3D genome misfolding due to repeat instability in neurodegenerative disease — Kristen Brennand & Jennifer Phillips-Cremins
• A plant small-molecule discovery platform to study neurodegeneration — Ankur Jain & Jing-Ke Weng
• Applying optical pooled screens to identify new therapeutic targets in ALS — Paul C. Blainey & Clotilde Lagier-Tourenne
• Bridging the translational gap: A novel adult human brain tissue system — Henner Koch & Deborah Kronenberg-Versteeg
• Gut macrophages and LRRK2: Anovel paradigm for Parkinson’s disease — Tim Bartels & Soyon Hong
• Homeostatic neuroprotection in ALS — Graeme Davis & Kira Poskanzer
• Identifying novel neurodegenerative pathways in rare pediatric disorders — Rebecca Ahrens-Nicklas & Elizabeth Bhoj
• Illuminating organelle dynamics in development and neurodegeneration — Sarah Cohen & Mohanish Deshmukh
• In vivo CRISPR screens to uncover regulators of neurodegeneration — Alejandro Chavez & Serge Przedborski
• In vivo forward genetic screens by CRISPR for neurodegeneration modifiers — Yang Hu & Stanley Qi
• Lipid dynamics and mitochondrial metabolism in neurodegenerative diseases — Pietro De Camilli & Hongying Shen
• Longitudinal full-length, single molecule RNA analysis in neurodegenerative — Robert Spitale & Leslie Thompson
• Membrane damage and repair in neurodegeneration — Jeremy Carlton & Adrian Isaacs
• Molecular convergence between genes and aging in neurodegeneration — Alessandro Ori & Michael Ward
• Molecular dissection of metabolic homeostasis pathways in neurons — Marc Hammarlund & Gulcin Pekkurnaz
• Neurolipid atlas — Martin Giera & Rik van der Kant
• Neuronal phenotypes of impaired nascent protein quality control — Wade Harper & Sichen Shao
• New roles of the proteasome in preventing neurodegeneration — Esteban O. Mazzoni & Christine Vogel
• Next generation neuropathology: proximity-proteomics of proteinopathies — Melissa E. Murray & Wilfried Rossoll
• Promoting neuronal cell death to mitigate widespread neurodegeneration — David Simon & Trent Watkins
• Regulation of mRNA and RNP granules by VCP in motor neuron degeneration — Stephanie Moon & Nils Walter
• Role of white matter and cerebrovascular aging in neurodegeneration — Ozgun Gokce & Mikael Simons
• Spatial analysis of aberrant RNA isoforms in ALS neuromuscular organoids — Mina Gouti & Nikolaus Rajewsky
• Synapse-microglia signaling mechanisms for proteostasis — Takanari Inoue & Shigeki Watanabe
• The mitochondrial RNA structurome as mediator of neurological diseases — Antoni Barrientos & Silvia Rouskin
• The physical biology of neurodegeneration — Liam Holt & Hemali Phatnani
• The role of Pink1/Parkin in the intestinal epithelium — Ming Guo & Elizabeth J. Videlock
• Understanding neuronal vulnerability to degeneration in Parkinson’s disease — Maria Soledad Esposito & Ignacio E. Schor
• Using antisense oligonucleotides to increase mRNA translation — Sergej Djuranovic & Timothy Miller
• Using computer vision to annotate Cryo-Electron tomograms of neurons — Wah Chiu & Serena Yeung

To learn more about our work at CZI, visit our website and follow us on Twitter.