For over 60 years, science has known the “what” of Down syndrome: an extra copy of chromosome 21. It is the most common genetic cause of intellectual disability worldwide. Yet, despite this long-standing knowledge, the “how” has remained largely a mystery. We have known the cause, but we haven’t fully understood the consequences—specifically, how that extra chromosome rewires the developing human brain.
It is time to highlight a shift in how we approach this condition. For decades, the focus has rightly been on social inclusion and managing physical health. But in the lab, we are now moving toward addressing the root causes of the intellectual challenges and potentially neurodegeneration that affect so many.
In our latest study published in Nature Medicine, a collaboration between Imperial College London and Duke-NUS Medical School, we set out to create the most detailed molecular map of the Down syndrome brain to date. By analyzing tissue from the critical developmental window of 10 to 20 weeks post-conception, we were able to trace the path from genetic cause to cellular consequence.
We discovered that the “noise” created by the extra chromosome isn’t random. We identified three specific gene regulators encoded on chromosome 21—BACH1, PKNOX1, and GABPA—that act as drivers. These factors are overactive in the brain cells of individuals with Down syndrome, disrupting hundreds of other molecular processes essential for learning and memory.
Crucially, we found that this process is not necessarily set in stone. Using “antisense oligonucleotides” (ASOs)—tiny synthetic molecules designed to interact with RNA—we were able to “dial down” the activity of these three genes in laboratory-grown human brain cells. The result was a partial restoration of normal gene activity.
This is a significant step forward. It opens new avenues for research into how we might address the cognitive challenges of the condition.
To be clear, this is a foundation for the future, not a cure available today. We still need to understand how these changes play out in more relevant living models. However, by pinpointing these specific targets, we have moved from a general understanding of the condition to a precise roadmap for potential therapy. This day we celebrate not only the resilience of the community but the exciting reality that science is finally catching up to their needs.
Neuroscience & Behavioural Disorders Signature Research Programme, Duke-NUS Medical School; Honorary Professor,Department of Brain Sciences, Faculty of Medicine, Imperial College London.
Professor Vincenzo De Paola’s research focuses on understanding the mechanisms of synaptic and axonal breakdown that drive cognitive decline in neurodegenerative diseases, and on identifying strategies to promote neural repair. His foundational work includes some of the first-ever dynamic observations of synapse formation, elimination, and regeneration in the living brain. This mechanism-focused approach has produced fundamental discoveries, with key findings published in Science and Nature Medicine and the recent development of a patented therapeutic strategy for Down syndrome. Professor De Paola’s work aims to translate these insights into effective treatments for both Down syndrome and the broader spectrum of neurodegenerative disorders.
Department of Brain Sciences, Faculty of Medicine at Imperial College London.
Dr Michael Lattke’s overarching research interest is to understand how genomic programmes in their interaction with external signals control cellular functions in brain development and disease. He is particularly interested in "omics" approaches to systematically study programmes controlling the functions of astrocytes, a major glial cell type, which has diverse functions critical for brain development and homeostasis. Astrocyte dysfunction has been implicated in many neurological disorders, including neurodegenerative disorders such as Alzheimer's disease. Dr Lattke’s long-term vision is to harness these genomic mechanisms to restore or enhance protective astrocyte functions as therapeutic strategy for such disorders.