A New Approach to Solving Neurodegeneration

Launching CZI’s Neurodegeneration Challenge Network

Neurodegeneration is one of society’s critical issues over the next 50 years. Millions of people worldwide suffer from neurodegenerative diseases, which include Alzheimer’s and Parkinson’s as well as ALS, Multiple Sclerosis, Huntington’s, and a diverse range of other conditions. Neurodegenerative diseases share the common feature that they involve a progressive degeneration and ultimately death of neurons, the key communication lines of our brain and nervous system. These are terrible diseases, ones that deteriorate the brain and body, taking away a person’s independence, cognitive capacities, personality, and sense of self. There are no effective therapies to prevent, cure, or treat most of these disorders.

The societal impact of these disorders is staggering. Alzheimer’s disease alone is the fifth most common cause of death for Americans above age 65, and the number of people with Alzheimer’s and related dementias is predicted to nearly triple — from 5 million people to 14 million people — by 2060. The profound human toll and suffering impacts everyone — patients, caregivers, family and friends. That’s why the Chan Zuckerberg Initiative is investing in a new approach to tackle neurodegeneration.

Not one, but hundreds of diseases

While we tend to think about neurodegenerative diseases as conditions like Alzheimer’s and Parkinson’s that are associated with old age, neurodegenerative diseases represent a diverse range across the entire lifespan, including diseases that afflict infants and children, like Spinal Muscular Atrophy; to diseases like ALS and Huntington’s that are often diagnosed in middle age. And for most neurodegenerative diseases, we now think that the initial disease processes begin decades before the symptoms emerge. There are hundreds of neurodegenerative conditions, with distinct features and causes — some are genetic; some share comorbidities with other diseases, like heart disease and diabetes; some come about from injury, and others result from side effects of treatments for other conditions, such as chemotherapy-induced neuropathies.

The CZI Neurodegeneration Challenge Network aims to take a new approach to tackling these diseases. The Challenge Network is an experiment, one we believe can have impact well beyond the investigators included. We recognize that this is not a problem we can solve alone — only when we work together can we truly solve the challenge of neurodegeneration. The Neurodegeneration Challenge Network has two goals. First, create a new collaborative, open-science centered approach to generate new ideas. Second, use those ideas to develop new approaches to make advances in our understanding of the fundamental biology of neurodegeneration.

In considering how CZI might be able to contribute to the global efforts to address these major challenges, we set out to learn more about the science in this field and current work being done across the space. To better understand the challenges and gaps, and also the progress and opportunities, we hosted a number of workshops and met with a broad range of stakeholders. We set out to listen and learn from scientists, both in the neurodegeneration field and adjacent areas, including those focused on basic research and clinical development; researchers at all levels from trainees to senior faculty; advocacy organizations, foundations and funders focused on neurodegenerative diseases; physicians; and most importantly, patients and family members who know these diseases better than anyone else.

What we learned from these efforts was that there are a lot of talented people working hard at cracking these diseases. It has not been for lack of effort, investment, hard work, or will that the field has struggled to develop therapies. So where does the problem lie? We came away focused on two key challenges. First, we still don’t fully understand the causes and underlying biology of these diseases. We have learned a lot and have ideas and working models, but these are complex diseases, and our mechanistic understanding is still relatively nascent. Second, the field collectively has suffered from a longstanding siloing of effort, models and approaches and this has held back progress. We need new ideas and perspectives on these disorders and approaches that are more integrative, collaborative, and multidisciplinary.

To help generate these new ideas and approaches, we’re investing $51.95 million in funding to launch the CZI Neurodegeneration Challenge Network, with nine new collaborative science teams and 17 early career investigators. Our goal is to establish a new kind of interdisciplinary collaborative network, one that brings a diversity of ideas and people into the field, supports them with well-validated tools and resources, and asks them to engage in studying these diseases within a different framework and from a different perspective. By bringing together new people and forging new types of collaborative interactions, we aim for the Challenge Network to be much more than the sum of its parts.

But research consortia are not a new idea in science. How will the Challenge Network be different?

Breaking down silos

The Challenge Network will bring together researchers from across different fields of neurodegeneration, with an emphasis on common mechanisms and approaches that may have cross-cutting impact for a broad range of neurodegenerative diseases. Traditionally, neurodegenerative diseases have been studied as specific diseases, with specialized fields of research, funding, support, and infrastructure. For example, Alzheimer’s researchers attend Alzheimer’s conferences, but rarely do they join Parkinson’s or ALS meetings (and vice versa). Likewise, clinicians and basic scientists work in largely separate domains. But the biology does not operate in silos or obey disease diagnostic categories.

Many neurodegenerative diseases share common genetics and underlying pathological features. For instance, many people who die with an Alzheimer’s diagnosis exhibit pathologies associated with Lewy body dementias, more typical of Parkinson’s. Likewise, in some families, the same mutations can be associated with either a diagnosis of ALS or frontotemporal dementia. A key goal of the Challenge Network is to break down some of these silos and encourage the field to reconceptualize the way we think about neurodegenerative diseases, moving away from the disease-focused approaches to a view of these disorders as a broad class.

This reconceptualization is modeled after a similar pivot in the cancer field, where there has been a shift from an organ-centered view of cancer as distinct diseases — breast cancer, lung cancer, pancreatic cancer — to a more integrated view of cancer as a class of disorders, with shared biology and underlying mechanisms, clinical features, and, in many cases, therapeutics. We can learn much from how the cancer field approached the challenge of understanding the broad range of cancers, and how a focus on underlying biology ultimately led to a range of new therapeutic strategies. The next scientific or therapeutic breakthrough for one disease may be triggered by an advance in a neighboring field.

CZI Science Program Officer Katja Brose speaks at an ASCB panel discussion on neurodegeneration.

Focusing on basic science

We have specifically chosen to focus the Challenge Network on fundamental biology as a complement, not an alternative, to existing efforts from other funders, disease foundations, and companies focused on more translational and clinically focused strategies. There is an understandable urgency for developing approaches to treat neurodegenerative diseases. At the same time, the intense and exclusive focus on delivering new drugs and treatments and haste to move from candidate targets to therapies can be problematic if it comes at the expense of a rigorous understanding of the underlying mechanisms. We see our focus on basic biology as a necessary foundation for ultimately being able to develop therapeutic strategies to prevent or treat these diseases.

Staying connected to clinical context

While the focus of the Challenge Network is on basic science, it’s critically important that the work of the Challenge Network stays closely connected with what’s happening to patients and with current clinical understanding. To that end, clinical mentoring will be a critical element of the Challenge Network. We want to assure that as we bring in new recruits to the field, they have access to up-to-date clinical information, resources and knowledge. Newcomers to the field bring the benefits of a fresh perspective, and by connecting them to clinicians and experts in neurodegeneration, they are able to benefit from a strong foundation and the expertise of the collective Challenge Network and community.

Considering the whole body, not just the the brain

Neurodegenerative disorders are disorders of the whole body, not just the brain and nervous system. Although defined as diseases involving degenerating neurons, we know that these disorders involve a broader range of cell types and systems. Clinical and epidemiological evidence have suggested roles for the immune system, gut, blood-brain barrier, and vasculature systems as contributing to neurodegenerative disease, but these research areas have historically attracted relatively less interest and funding. We know there are links between neurodegenerative diseases and metabolic disorders, like diabetes and heart disease. Genetic risk is critical, but we also know that the environment and one’s life experiences contribute to these diseases in some way. And we’re only starting to understand the biological mechanisms involved. There is a massive opportunity to accelerate our understanding of neurodegeneration by bringing in expertise and talent from other fields such as immunology, oncology, and metabolism.

Broadening the search space for new mechanisms and approaches

Historically the neurodegeneration field has focused on a relatively narrow range of mechanisms and strategies. It’s time to widen the search space. We see particular promise coming from recent advances in genetics, which are shining a spotlight onto new genes and opening up new windows into the biology that underlies these disorders. For instance, recent genetic studies have pointed to the role of immune mechanisms and inflammation in a number of neurodegenerative disorders. But genetics can only go so far, and we need new techniques and methods to unravel the corresponding cellular and physiological mechanisms. New, more sophisticated methods for cell biology, molecular biology, and biochemistry that allow us drill into underlying biology at higher resolution, along with engineering, bioinformatic, and computational methods, will be needed to understand the complex data that result from these more sophisticated methods.

The Challenge Network will function as a type of incubator and test lab for our engineering and computational biology groups, bringing together basic scientists, physicians, computational scientists, and engineers to work together on identifying common challenges and opportunities for developing data- and engineering-aligned solutions and openly accessible tools that will benefit the whole community.

Introducing the new class of CZI Investigators

We initiated the CZI Neurodegeneration Challenge Network with an open call through two Request for Applications in February 2018 and received over 700 applications total. We specifically aimed to recruit cross-over applicants from other fields; no preliminary data or even previous research in neurodegeneration was required. Applications were evaluated through a rigorous three-phased expert review process. We chose this open approach with the aim of offering an open opportunity for new entrants to the field to come forward with their most creative and innovative ideas, and were gratified with the level of response from the community. We are pleased to announce the first class of the CZI Neurodegeneration Challenge Network, including 17 awardees of the CZI Ben Barres Early Career Acceleration award and nine groups awarded the CZI Collaborative Science award.

Ben Barres speaks at a Neurodegeneration Challenge Network planning workshop in 2017.

Fostering the next generation of neurodegeneration researchers

Changing the field and making progress on solving these diseases will require bringing a new generation of scientists into the field. The Ben Barres Early Career Acceleration Award is specifically aimed at early career scientists who are in the first years of starting their own research labs. The award is named for the luminary neuroscientist Ben Barres, who died in late 2017. Ben was a fierce advocate for young scientists, mentorship, and diversity in science, and also a key advisor CZI and our neurodegeneration program. He doggedly challenged those around him to think differently, not only about science, but also about the ways the members of the scientific community practice science and engage with each other. In this and so many other ways, Ben embodied spirit that we hope the Challenge Network will nurture in these new investigators and more broadly, in the next generation of scientists.

To learn more about our work in science and to stay updated on funding opportunities, visit our website, where you can sign up for our mailing list. You can also follow us on Twitter. To learn more about our science team, follow the CZI science blog. And you can always reach us at science@chanzuckerberg.com.

Katja Brose, Science Program Officer, Chan Zuckerberg Science Initiative

Katja Brose, Ph.D., is a Science Program Officer at the Chan Zuckerberg Initiative, where she leads CZI’s efforts in neurodegenerative disease. She received her PhD from UCSF, where she studied developmental and molecular neuroscience. Prior to joining CZI, she was part of the editorial team at Cell Press, where she was Editor-in-Chief of the journal Neuron and a member of Cell Press management team. She is passionate about basic science and its potential impact for understanding and treating disease.