Isogenic patient stem-cell lines

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Frank Soldner, Rudolf Jaenisch and colleagues (Whitehead Institute, MIT). Cell 146(2):318–331, 2011. PubMed lists NIH extramural grant support; the funders were not read from the paper.

What happened

Stem cells made from patients (landmark 32, landmark 47) differ from healthy controls in thousands of ways beyond the disease gene. For a late-onset disease with subtle cell changes, that background noise can hide the real effect. The team used zinc finger nucleases (engineered DNA-cutting enzymes) to edit point mutations in the alpha-synuclein gene (SNCA) in human pluripotent stem cells. They introduced A53T and E46K into embryonic stem cells, and corrected A53T in iPSCs from a patient. That produced sets of "isogenic" cells: identical in every respect except the Parkinson's-linked variant. Edited lines kept a normal karyotype and pluripotency, and corrected cells still made tyrosine-hydroxylase-positive dopamine neurons. Expression profiling found that donor genetic background mattered more than editing. The paper shows the method works; it does not report a disease phenotype in the neurons.

Why it moved us toward a cure

Isogenic pairs let a lab say that a difference in the dish is caused by the mutation, not by who donated the cells. That is needed to screen drugs and to test whether a phenotype is real. The approach scaled later into shared collections (landmark 273).

Outcome

Advanced. Isogenic design is now standard in the field. It does not change the limits of cultured cells: they are young, and lack ageing and other cell types.

Sources

• Soldner et al., Cell 2011;146:318–331, DOI 10.1016/j.cell.2011.06.019 (abstract via Europe PMC, PMC3155290)
• Full text, PMC3155290: mutations A53T and E46K (only the first 100,000 characters of the page were read)
• Correction: Cell published an erratum on 19 Aug 2011 (DOI 10.1016/j.cell.2011.07.035, listed by Crossref and Europe PMC). The notice itself could not be read, so what it corrects is unknown. No retraction was found.
• Not yet verified: what the erratum corrects; the funders and the Sangamo affiliations of the ZFN authors; the last 3,500 characters of the full text; independent replication of the editing method (it has since been widely reused, but no source was checked).