From Jérôme Lejeune's Discovery to Modern Research for a Cure
For centuries, Down syndrome was shrouded in misunderstanding and stigma. The transformation in our understanding began with a groundbreaking discovery in 1958 that would revolutionize both genetics and medicine.
For centuries, Down syndrome was shrouded in misunderstanding and stigma, often attributed to vague maternal impressions or racial heredity. The transformation in our understanding began with a groundbreaking discovery in 1958 that would revolutionize both genetics and medicine.
This article traces the fascinating journey from the initial identification of the genetic cause of Down syndrome by Jérôme Lejeune to today's cutting-edge research aimed at understanding and potentially treating the effects of trisomy 21. We'll explore how one man's dedication to science and patients opened a new chapter in human genetics and how modern researchers are building upon his legacy using revolutionary technologies.
In the 1950s, the scientific community knew that Down syndrome was congenital but had no understanding of its origin. The condition was still referred to by the outdated and misleading term "mongolism," reflecting the profound confusion about its causes. Enter Jérôme Lejeune, a French pediatrician and geneticist working under Professor Raymond Turpin, who became determined to solve this medical mystery.
Until 1956, scientists incorrectly believed humans had 48 chromosomes. That year, Tjio and Levan established the correct number: 46 4 . This critical piece of the puzzle provided Lejeune with the baseline he needed.
Lejeune's colleague, Marthe Gautier, brought specialized cell culture techniques from the United States that allowed for better chromosome analysis 1 4 . Her work developing laboratory capabilities was essential to the discovery.
Lejeune made a historic observation in his laboratory notebooks: he had identified 47 chromosomes in a child with Down syndrome 1 . This was the first time a chromosomal abnormality had been linked to a developmental condition.
The discovery was transformative—not only did it provide a scientific explanation for Down syndrome, but it also helped dispel the stigma that had plagued families for generations 4 . No longer could parents be blamed for their child's condition through theories about hereditary degeneracy or maternal impressions.
French pediatrician and geneticist who discovered the chromosomal basis of Down syndrome in 1958.
Key contributor who developed the cell culture techniques essential to the discovery of trisomy 21.
Trisomy 21 occurs when an individual has three copies of chromosome 21 instead of the usual two. This genetic dosage imbalance affects multiple bodily systems and leads to the characteristic features of Down syndrome. But what makes this extra chromosome so impactful?
Chromosome 21 contains an estimated 200-300 genes 3 . The overabundance of these genes disrupts normal development and function through several mechanisms:
Congenital heart defects occur in approximately 50% of individuals with Down syndrome, with atrioventricular septal defects being the most common 6 .
Affects approximately 50% of individualsMuscle hypotonia (low muscle tone) is present in nearly all newborns with Down syndrome and contributes to delayed motor development 6 .
Present in 95% of newbornsGastrointestinal abnormalities such as duodenal atresia, imperforate anus, and Hirschsprung disease occur more frequently 6 .
12% of Hirschsprung patients have Down syndrome"For me, this research is like a detective story." - Jérôme Lejeune
Today's scientists are the detectives following in his footsteps, armed with powerful new tools to unravel how an extra chromosome 21 creates such wide-ranging effects.
Recent research has focused on understanding how trisomy 21 affects the earliest stages of human development. A 2024 study published in Frontiers in Cellular Neuroscience used induced pluripotent stem cells (iPSCs) from individuals with Down syndrome to model neural induction—the process where stem cells first become nerve cells 5 .
The researchers discovered that trisomy 21 impacts development much earlier than previously thought, with over 1,300 genes showing different expression patterns during early neural development 5 . Key pathways affected include:
This early disruption likely sets the stage for later neurological differences observed in individuals with Down syndrome.
A groundbreaking 2025 study in Nature Communications took an even broader approach, analyzing how trisomy 21 affects people differently throughout life . By examining the transcriptome, proteome, metabolome, and immunome of hundreds of research participants, the team identified eight distinct biological signatures that change with age in Down syndrome.
The research revealed that trisomy 21 isn't a static condition—its effects evolve throughout life:
These findings explain why individuals with Down syndrome have different health needs at different ages and suggest that future treatments might need to be tailored to specific life stages.
Understanding gene expression patterns
Early brain development impacts
Heart defect mechanisms
Reduced cancer risk factors
To understand how modern genetics research works, let's examine a specific experiment in detail. The 2024 stem cell study mentioned earlier provides an excellent example of contemporary approaches to understanding trisomy 21 5 .
Researchers started with fibroblasts (skin cells) from a 24-year-old female mosaic for trisomy 21 and reprogrammed them into induced pluripotent stem cells (iPSCs)—adult cells that have been genetically "rewound" to an embryonic-like state 5 .
These iPSCs were then guided through a carefully orchestrated 17-day differentiation process:
At multiple timepoints (Day 6, Day 10, and Day 17), researchers extracted RNA and performed bulk RNA sequencing to see which genes were active 5 .
Using sophisticated bioinformatics tools, the team compared the gene expression patterns between trisomy 21 cells and euploid (typical) controls across the different developmental stages.
The experiment revealed that trisomy 21 disrupts early neural development in several crucial ways:
Appears almost immediately, suggesting it might fundamentally influence later development
Significantly dysregulated, potentially affecting how the brain forms its complex structures
Genes turning on at the wrong times disrupts the carefully choreographed sequence of neural development
This research provides crucial insights into why early intervention might be particularly important for supporting neurodevelopment in infants with Down syndrome.
| Tool/Technique | Function | Research Application |
|---|---|---|
| Induced Pluripotent Stem Cells (iPSCs) | Reprogrammed adult cells that can become any cell type | Model early developmental processes like neural induction 5 |
| RNA Sequencing | Comprehensive analysis of gene expression | Identify which genes are active during development 5 |
| Multi-omic Analysis | Simultaneous study of genes, proteins, metabolites, and immune cells | Create comprehensive biological profiles across lifespan |
| Karyotyping | Visualization and counting of chromosomes | Initial diagnosis and identification of chromosomal abnormalities 4 |
| Cre-loxP System | Targeted chromosome elimination | Study specific chromosome contributions by removing them 8 |
Chromosome visualization technique used by Lejeune to discover trisomy 21
More precise chromosome mapping using fluorescent probes
High-throughput analysis of gene expression and genetic variations
Comprehensive genome, transcriptome, and epigenome analysis
Integration of multiple data types and resolution at single-cell level
| Body System | Common Conditions | Prevalence | Research Insights |
|---|---|---|---|
| Cardiovascular | Atrioventricular septal defects, Ventricular septal defects | Up to 50% of individuals 6 | Associated with mutation in non-Hsa21 CRELD1 gene 6 |
| Gastrointestinal | Duodenal atresia, Hirschsprung disease, Celiac disease | 2% have Hirschsprung disease 6 | 12% of Hirschsprung patients have Down syndrome 6 |
| Neurological | Infantile spasms, Alzheimer's disease, Intellectual disability | 5-13% have seizures 6 | 50-70% develop dementia by age 60 6 |
| Hematological | Transient myeloproliferative disorder, Leukemia | 10% have transient leukemia 6 | 10x higher risk of leukemia; associated with GATA1 gene 6 |
| Immune System | Autoimmune conditions, Respiratory infections | Highly prevalent | Chronic immune activation and inflammation across lifespan |
The National Institutes of Health has launched the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) to accelerate research 9 . This ambitious initiative focuses on:
Understanding fundamental biology of chromosome 21 and its effects on development and health.
Building large-scale study groups across the lifespan to track health outcomes and identify patterns.
Testing interventions for co-occurring conditions and potential therapies to improve cognitive function.
Research into the significantly lower rates of most solid tumors and coronary heart disease in individuals with Down syndrome 3 .
Creating interventions for cognitive challenges based on understanding of neurological differences.
Research into the increased Alzheimer's risk and premature aging observed in adults with Down syndrome 6 .
Developing healthcare guidelines tailored to different life stages of individuals with Down syndrome.
Jérôme Lejeune's story is one of both triumph and tragedy. His discovery earned him international acclaim, including the Kennedy Prize from President John F. Kennedy and the William Allan Award 1 4 . Yet, he was deeply troubled that his discovery led to prenatal testing and selective abortion, writing to his wife that he had "lost my Nobel prize in Medicine" because of his anti-abortion stance 1 . This devout Catholic would later become the first president of the Pontifical Academy for Life and is now declared "Venerable" in the Catholic Church 1 7 .
Despite these complex ethical dimensions, Lejeune's fundamental insight—that Down syndrome has a specific genetic cause—continues to drive research forward. Today's scientists, building on his legacy, are no longer simply describing the condition but actively working to understand its mechanisms and develop interventions that could improve quality of life.
The journey from Lejeune's karyotype analysis to modern multi-omic studies represents more than technical progress—it reflects an evolving understanding of human diversity and potential. As research continues to unravel the complexities of trisomy 21, we move closer to a world where people with Down syndrome might not only receive better medical care but also see their unique attributes valued and understood.