A study published in Molecular Systems Biology introduces iPS2-seq, a groundbreaking technology poised to reshape the way researchers investigate the human genome. The work, led by Elisa Balmas from the laboratory of Alessandro Bertero at the University of Turin, is the result of three major international projects - the Armenise-Harvard Career Development Award, the Single Ventricle Research Fund and the ERC Starting Grant TRANS-3 - and was carried out in collaboration with IMBA in Vienna.
In recent years, genetics has identified thousands of variants potentially linked to disease. Yet determining how each gene influences organ development and function remains one of biology’s greatest challenges. iPS2-seq offers a powerful new approach: by using human pluripotent stem cells capable of forming organoids - miniature structures that mimic human tissues - researchers can examine many genes at once within a single experiment.
Alongside the experimental platform, the team also developed catcheR, a software tool designed to streamline both the planning and analysis of iPS2-seq studies, making the technology easier to adopt across the scientific community.
iPS2-seq enables the simultaneous study of dozens of genes, the creation of detailed molecular atlases through single-cell sequencing, and the observation of gene function at specific stages of development by switching genes on and off in a controlled manner. It can even capture multiple layers of information within the same cell, including gene expression, DNA structure and key regulatory proteins.
To demonstrate the platform’s potential, the researchers applied it to genes associated with congenital heart disease, which affects roughly one newborn in 100. Their work revealed a crucial role for the gene SMAD2 during early cardiac development: when temporarily silenced, cells no longer progress toward becoming cardiomyocytes but instead shift toward other lineages such as fibroblasts or epicardial cells.
The discovery clarifies key mechanisms underlying hereditary heart conditions and opens promising avenues for personalized medicine. Future phases of the project, funded by Telethon Foundation and Fondazione Cariplo, will extend the technology to lesser-known genes linked to rare congenital heart defects.

“With iPS2-seq, we can finally investigate gene function in human stem cells and complex tissue models in a systematic way,” said Bertero. Balmas added that the method could help identify therapeutic targets for genetic diseases, accelerating progress toward precision medicine.