Our new perspective article is published in Nature Reviews Genetics!

July 27, 2025

The article, "Decoding cell fate: human models reveal how SMAD2 variants shape development," discusses a recent work by Ward et al. from Harvard Medical School, who used genome engineering to create isogenic human iPSC lines with patient-derived SMAD2 variants. This approach allowed them to dissect the transcriptional and epigenetic consequences of SMAD2 mutations in a human context—something that's often impossible to address in animal models due to early embryonic lethality.

This article examines how human stem cell models are revolutionizing the current understanding of congenital heart disease and developmental biology. The article, "Decoding cell fate: human models reveal how SMAD2 variants shape development," discusses a recent work by Ward et al. from Harvard Medical School, who used genome engineering to create isogenic human iPSC lines with patient-derived SMAD2 variants. This approach allowed them to dissect the transcriptional and epigenetic consequences of SMAD2 mutations in a human context—something that's often impossible to address in animal models due to early embryonic lethality. This work highlights the power of human iPSC models and genome editing to bridge the gap between genetic variants and their functional consequences. It's a call to design experimental models that truly reflect human complexity, paving the way for more precise diagnostics and therapies.

Read the full article: http://tiny.cc/naturerevgenetics

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