Alzheimer’s Disease and brain awareness month in June provides a significant opportunity to recognize the critical importance of brain research and its profound impact on global health. Through an open science model, SGC is dedicated to unravelling the complexities of neurological disorders that affect over 1 billion people worldwide – diseases that include Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis (ALS), and rare neurodegenerative diseases like Huntington’s disease.

We proudly host five SGC-affiliated and distinguished experts in the field across SGC sites and disciplines. Their work, either within SGC or its spin out initiatives, exemplifies the dedication and innovation necessary to understand and treat neurological disorders. 
In this special blog edition, we delve into the diverse realms of their research scope, their transformative influence on brain disorders, the alignment of these projects to open science principles and the significance of collaboration and outreach.

Unraveling the Neurological Tapestry: From the Familiar to the Rare

In the vast landscape of neurological disorders, some conditions loom large in public awareness while others remain in the shadows. From the familiar to the rare, our researchers in SGC are driven to uncover the underlying mechanisms of neurological disorders that afflict millions worldwide, connecting the dots to unravel the complete neurological tapestry and accelerate the discovery efforts toward treatment.

Alzheimer’s disease (AD) is a brain disorder and is considered the most common cause of dementia among the elderly. It is estimated that over 6 million Americans, aged 65 and older, are affected with no cure to effectively treat or prevent the onset of the disease. The past two decades of drug discovery efforts in AD have been focused on a few therapeutic hypotheses with little success in developing game-changing therapies for human use. 

To this end, the National Institute on Aging has launched an initiative, called TREAT‐AD (TaRget Enablement to Accelerate Therapy Development for AD), which aims to improve and diversify the portfolio of AD drug targets by accelerating the characterization and experimental validation of next-generation therapeutic targets and integrating them into drug discovery campaigns.

Alison Axtman, Associate Professor at SGC at the University of North Carolina at Chapel Hill (UNC) and member of SGC TREAT‐AD Center, has focused her research on creating tools to characterize the role of underexplored proteins implicated in neurodegenerative and neurodevelopmental disorders. Her team has delivered several small drug-like molecules, called chemical probes, which are used to interrogate the function of underexplored human protein kinases. A recent example of this work is the identification of two chemical probes which target CDKL5; a protein associated with a rare, neurodevelopmental disorder called CDKL5 deficiency disorder.

“There are proteins that when modified using a high-quality small molecule tool could be disease-modifying”, says Alison, who has recently been funded to work in AD and ALS research. “Chemical tools could be further developed into drugs that would represent an improvement on current, limited therapies that address late-stage symptoms and lead to modest improvements in quality of life.”

Similarly, Levon Helabelian, Assistant Professor at SGC at the University of Toronto, uses structural and biophysical tools to study three human RNA helicases (DDX1, IFIH1 and DHX58), which seem to play a role in AD progression. His team generates Target Enabling Packages (TEPs); high‐quality experimental reagents and informatic outputs, including proteins and small-molecule chemical probes, needed to validate the protein target for AD and enable parallel and unencumbered research in the field.

“The reagents and data generated in this project will help accelerate the identification of small-molecule chemical probes to further evaluate their role in AD”, says Levon who is also actively involved in the TREAT‐AD consortium.

On the other side, while diseases like Alzheimer's and Parkinson's dominate the spotlight, we recognize the urgent need to also shed light on less prevalent conditions that often go unnoticed. Huntington's disease (HD) is one of these rare disorders, which occurs in only 3 out of 100,000 people. At the forefront of our exploration, Rachel Harding, Assistant Professor at SGC at the University of Toronto, directs her focus on HD. By studying the huntingtin protein, which is mutated in individuals with HD, Rachel seeks to unravel the mysteries surrounding this devastating disorder. 

“We are trying to paint a comprehensive picture of huntingtin's structure-function relationship, through a multidisciplinary approach combining cryo-EM, modeling, and other advanced techniques”, says Rachel.

Bridging the Gap Between Structural Biology and Stem Cell Research

Treating neurological disorders has been slow mostly because of the complexity of the human brain combined with limited access to human brain tissue. This hindering progress in deciphering this system, made Tom Durcan, Associate Professor at SGC Neuro at McGill University, believes that brain disorders could be made treatable if we worked with more relevant human models. 

“During my early research career, I would work with cancer cells to study Parkinson’s disease, and it always baffled me why we couldn’t work with human neurons: the cells affected in the disease”, says Tom.

As such, he established the Early Drug Discovery Unit (EDDU) at Neuro to better understand these disorders and work with partners to accelerate the discovery of therapies for the patients affected. By utilizing induced pluripotent stem cells (iPSCs), his team generates many of the different types of human brain cell on a dish and focuses their efforts on understanding why diseases like Parkinson’s disease, ALS, and neurodevelopmental disorders arise.

From crisis to progress

While we have harnessed the power of structural biology and stem cell research, we recognize that our journey toward understanding and treating neurological disorders requires more hands on deck with different approaches. 

The use of poorly characterized antibodies has posed significant challenges, contributing to the reproducibility crisis and hindering the development of therapeutics for brain-related diseases. Information regarding the success rates of commercial antibodies and their performance based on the technology used to produce them is predominantly anecdotal. Thus, proper characterization of antibodies can be challenging, costly and not accessible to all scientists. 

Toward this goal, Carl Laflamme along with Peter McPherson leads the YCharOS (Antibody Characterization through Open Science) effort at the SGC Neuro, which aims at identifying high-quality renewable antibodies for protein targets involved in neurodegenerative diseases. This initiative is a partnership of academics, funders, ten commercial antibody manufacturers, and two knockout cell line providers who have agreed on a standardized genetic approach using knockout cell lines to assess antibody performance in Western blot, immunoprecipitation, and immunofluorescence. 

“We are providing the neuroscience community with antibody characterization reports to help them select high-quality antibodies and enable reproducible research”, says Carl, whose team has prepared antibody characterization reports for 75 distinct proteins involved in ALS, Parkinson’s disease and AD within the last three years of YCharOS operation. “We are now poised to use the high-quality antibodies we identified to dive into the biology of many of the poorly characterized proteins linked to neurodegenerative diseases. For example, there are around 30 proteins genetically implicated in ALS, but only 4 are well-studied. By using high-quality antibodies, we identified and working with stem cell lysates generated at the SGC Neuro EDDU, we have now been able to uncover unexpected connections between some of them.”

Embracing Open Science and Collaborations

Toward the pursuit of understanding these complex brain disorders and developing effective therapies, all scientists in SGC are committed to the principles of open science, fostering collaboration, knowledge exchange, and reproducibility. 
Thomas stresses the transformative power of open science in driving higher research standards, encouraging scientists to engage with the wider community. 

“Open science goes beyond just being a concept. It means finding ways every day to work with others, to share our work, to hear about the work of others, and to ensure the research we do is of the highest standard to be reproduced anywhere else in the world. By opening ourselves up, it forces us to be better and to do better. For too long, scientists have been afraid to engage with the wider community and open science forces us to move outside of our comfort zone. Open science affords us this chance to get people to tune in and engage.”

Recognizing that progress is accelerated through collaboration and data sharing, Alison and Levon emphasize the urgent need for therapies, highlighting the importance of collective efforts and shared findings. “There is an urgent need for therapies and siloed science is not the path that will get us there”, Alison says while Levon adds “Under SGC's Open Science policy, all structural data and chemical probes are freely accessible without any usage restrictions or publication delays”.

Additionally, research initiatives such as YCharOS exemplify how antibody manufacturers and scientists can benefit from the open partnership since they can upload characterization data on their website and have access to all data for antibody selection.

As Carl explains “YCharOS works in an open science ecosystem with 11 industry partners, granting agencies, academic participants and pharmaceutical companies. This partnership is successful because the data is openly shared between all stakeholders, without restriction on use.” 

Collective minds with a singular vision

Their commitment to open science not only accelerates scientific advances but also encourages transparency, collaboration, and engagement with the broader research community. By fostering partnerships with experts in the field and sharing resources, SGC contributes to uniting researchers, scientists, and clinicians in a common pursuit of scientific breakthroughs. 

“Brain disorders are one of the most complex and challenging problems of our time, which means we must collaborate and be open in what we do if we want to succeed. Open science is a core tenet of how we operate and from our protocols to cell lines and assays, we try to make everything we do as accessible to interested users and partners everywhere so they can work alongside us, as two or more hands are always better than one.” Tom says.

Within the SGC, collaborations like the one between Alison's and Levon's groups synergistically leverage their respective expertise and methodologies by combining the power of medicinal chemistry and structural biology respectively. In addition, In the field of HD research, Rachel has cultivated an extensive collaborative network. Recognizing the significance of collaboration, Rachel emphasizes how sharing samples of her huntingtin proteins with fellow researchers in the field, serves as vital tools for various applications, ranging from basic biochemical studies to pre-clinical assay development. 

Beyond academia, SGC is always trying to encompass pharmaceutical companies, funders, and the broader scientific community to create a collective force for progress. For example, the engagement and collaboration between groups from TREAT-AD consortium contributes to gain access to additional resources and invaluable data that enhance the quality and depth of our research. Similarly, collaborating with industry partners and adhering to open science principles, YCharOS is setting a new standard for antibody characterization and paving the way for science to become a successful converge between business and science.

Science for all: openness, outreach, and engagement in brain research

Through collective effort, our five featured scientists seem to go above and beyond to ensure their research reaches the public domain and engage with the community through various outreach approaches. Driven by their commitment to open science, they adopt proactive strategies to disseminate their work and make it accessible to all.

Alison and Carl prioritize the swift sharing of their findings by posting their publications on pre-print servers and open access journals. Alison makes her chemical probes available to the broader community through the SGC website, while Carl shares openly their antibody characterization reports, enabling researchers worldwide to utilize these resources without restrictions. Similarly, Rachel contributes to open repositories, making essential renewable tools like plasmids widely available to the scientific community. This commitment to collaboration fosters an environment of openness and accelerates progress in HD research.

Levon emphasizes the importance of effective communication and engagement. “I encourage my team to disseminate their research findings through various channels, including social media, conferences, and publications. By proactively sharing our work with the scientific community and the broader public, we ensure that our research has a broader impact and can inspire further advancements in the field.”

Rachel extends her outreach beyond the lab by serving as an editor and ambassador for HDBuzz, a platform that delivers plain-language news articles on the latest scientific updates to HD patient families. This dedication to communicating complex scientific concepts in an accessible manner helps bridge the gap between researchers and the wider community.

Furthermore, in response to the challenges posed by the pandemic, Tom’s team demonstrated adaptability and innovation. Unable to conduct in-person training, they developed a video recording infrastructure in the lab, allowing them to capture and share their methods and protocols. This enabled them to continue their stem cell training workshops and expand their reach through The Neuro's YouTube channel. With the support of Neuro’s TOSI Grassroots initiative, they were able to create a comprehensive video collection in multiple languages, ensuring that their methods are widely accessible to researchers worldwide.

Advancing the SGC’s mission

The unwavering commitment of all the SGC scientists featured in this blog to unravel the mysteries of neurological disorders, and their focus on proteins implicated in these conditions directly contributes to the SGC's mission of discovering a chemical probe for every human protein. 

By targeting proteins associated with neurodegenerative and neurodevelopmental disorders, many of which lack a chemical probe, these scientists are pioneering crucial advancements in our understanding and treatment of these complex conditions. 

Furthermore, their efforts in generating targeted TEPs and chemical probes, as well as their evaluation of new hit-finding strategies, greatly support the SGC's overarching goal of accelerating drug discovery through open science collaboration.

Through their collaborative and interdisciplinary approach, across all SGC sites, they are forging a new era of scientific research that holds the promise of brighter futures for individuals affected by neurological disorders. We are looking forward to what the future holds for all this significant work in SGC.

Further reading:
Alison’s publications on CDKL5: Discovery of a Potent and Selective CDKL5/GSK3 Chemical Probe That Is Neuroprotective - PubMed (nih.gov)
Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology | bioRxiv
Summary of efforts of SGC TREAT-AD center: Open drug discovery in Alzheimer's disease - PubMed (nih.gov)
Ycharos preprint: Assessing the performance of commercial reagent antibodies | bioRxiv