Exploring the scientific breakthroughs and challenges in diagnosing and treating rare diseases through cutting-edge technologies and collaborative research.
Imagine a health puzzle so complex that it takes doctors an average of five years to solve, a journey through countless consultations and dead ends. This is the reality for millions of people living with rare diseases worldwide 3 . While each of these over 7,000 conditions is uncommon individually, collectively they form a significant public health challenge, affecting an estimated 20 million people in China and over 300 million globally 1 4 .
For decades, these conditions remained medical mysteries, with most having no approved treatments and patients often facing misdiagnosis and misunderstanding. Today, we stand at a revolutionary moment where cutting-edge science is beginning to illuminate these shadows, offering hope through precision medicine and innovative technologies that are reshaping our approach to diagnosis and treatment.
A disease is classified as "rare" when it affects a small percentage of the population. In China, this is defined as having a birth incidence of less than 1/10,000, a prevalence of less than 1/10,000, or affecting fewer than 140,000 patients 1 . The European definition sets the threshold at fewer than 1 in 2,000 people 3 . While this might suggest these conditions are insignificant, the opposite is true—their collective impact is substantial.
The statistics are staggering: approximately 80% of rare diseases are genetic in origin, meaning they are caused by alterations in our DNA 1 3 . The remaining include rare cancers, autoimmune disorders, and other conditions with complex causes. Despite significant advances, pathogenic gene variants have only been identified in 20%–40% of these conditions, leaving most partially or completely unexplained 1 .
Known Rare Diseases
People Affected in China
With Genetic Cause
For rare disease patients and their families, the journey to diagnosis often resembles an epic odyssey—lengthy, exhausting, and filled with uncertainty. This path, often called the "diagnostic odyssey," involves navigating through healthcare systems where expertise is fragmented and awareness is limited 3 .
Women: 5.4 years
Men: 3.7 years
"One does not immediately accept a diagnosis. The mind needs time to process and understand things."
— Psychologist supporting patients with serious chronic illnesses 4
The psychological impact of this uncertainty cannot be overstated. As one psychologist who supports patients with serious chronic illnesses notes, the process involves "highs and lows, often repeating in cycles," and that seeking early support can be crucial for coping 4 .
For years, genetic research has predominantly focused on the 2% of our genome that codes for proteins—the building blocks of our bodies. Yet the remaining 98%, once dismissed as "junk DNA," is now emerging as critical to understanding disease 1 . This non-protein-coding genome contains crucial regulatory elements that control how genes are expressed, and nearly 93% of disease-associated genetic variants fall within these regions 1 .
This revelation has sparked a fundamental shift in research approaches. Scientists are now looking beyond simple Mendelian inheritance patterns, where a mutation in a single gene causes disease, to more complex scenarios including oligogenic inheritance (where variants in multiple genes interact), gene-environment interactions, and epigenetic modifications that alter gene expression without changing the underlying DNA sequence 1 .
Protein-coding genes: 2%
Non-coding regions: 98%
To unravel this complexity, researchers are adopting systems biology approaches that integrate multiple layers of biological information. This "multi-omics" strategy combines data from the genome (all our genes), transcriptome (gene expression patterns), and phenome (all observable traits), creating a more comprehensive picture of health and disease 1 .
Analysis of all genes and their functions
Study of gene expression patterns
Characterization of all observable traits
These integrated approaches are particularly powerful for rare diseases. By analyzing how different biological scales interact, scientists can identify patterns that would remain invisible when examining any single layer in isolation. As noted in the Shuangqing Forum summary, "These integrated multi-level data approaches provide new insights into the characteristics of undiagnosed and rare diseases, thereby facilitating the implementation of next-generation sequencing in clinical diagnosis" 1 .
The revolution in rare disease research is powered by an array of sophisticated tools and technologies. These reagents and platforms enable scientists to ask questions that were previously impossible to explore.
Function: Patient-derived reprogrammable cells
Application: Create disease models for conditions too rare for animal models
Function: Precision DNA modification
Application: Determine pathogenicity of variants; create genetically corrected cell lines
Function: High-throughput DNA/RNA analysis
Application: Identify disease-causing variants; reduce diagnostic odyssey
Function: 3D mini-organs derived from stem cells
Application: Model tissue-level disease processes in human background
Researchers collect easily accessible cells from a patient, typically skin cells or blood cells.
These adult cells are "reprogrammed" in the laboratory using specific factors that turn back their developmental clock, transforming them into induced pluripotent stem cells (iPSCs).
Researchers direct these iPSCs to become the cell types affected by the rare disease—whether neurons, heart cells, or liver cells—creating a "patient-in-a-dish" model.
Using CRISPR-Cas9 gene-editing technology, scientists create genetically corrected versions of the same cells by fixing the disease-causing mutation.
By comparing the diseased cells with their genetically corrected counterparts, researchers can pinpoint exactly how the genetic mutation leads to cellular dysfunction.
No single researcher or institution can solve the challenge of rare diseases alone. Recognizing this, the scientific community is increasingly embracing collaborative models. The establishment of national rare disease cohorts and biobanks, such as the GSRD-100KWCH project launched by the West China Hospital of Sichuan University, represents a crucial step forward 1 . These resources allow researchers to study larger patient populations than would be possible at any single institution.
Rare As One Network: 94 patient-led organizations
Engaging 6,000+ researchers and 150+ projects 5
International research networks are also addressing the critical challenge of genetic diversity in rare diseases. As noted in recent analyses, "rare disease genetic variation tends to cluster within different populations, geographic locations, and ancestry groups" 7 .
This has led to a push for global clinical trials that can engage diverse patient populations, ensuring that research findings and resulting treatments are relevant to all affected communities.
The journey to unravel the mysteries of rare diseases is evolving from a scattered pursuit to a coordinated scientific campaign. While challenges remain—from the high costs of therapy development to ensuring equitable access—the progress is undeniable. What was once a landscape of diagnostic dead ends is now illuminated by the lights of genomic medicine, stem cell technology, and artificial intelligence.
"The landscape for rare disease drug development has changed significantly in recent years," with scientific advances making it "possible to develop treatments that were previously out of reach."
— Industry expert 6
The future of rare disease research lies in continued collaboration—among basic scientists, clinicians, patients, industry partners, and policymakers. As we strengthen this ecosystem, we move closer to a world where the diagnostic odyssey is shortened, where targeted treatments are accessible, and where the term "rare" no longer means "overlooked." In the words of the Shuangqing Forum participants, this requires "multidisciplinary and multisectoral cooperation" to establish frameworks that effectively address these complex conditions at scale 1 . Through these united efforts, the scientific community is steadily turning the impossible into the inevitable, ensuring that every patient, no matter how rare their condition, has the prospect of accurate diagnosis and effective treatment.