Gene editing technique makes disease study almost as easy as flipping a switch

Author: Holly Wobma, 08/05/14

Imagine you are about to interview someone, and rather than receiving a full reference letter, your candidate is described with but a single word. Do you think you’d get the whole picture?

Of course you wouldn’t, but depending on the word chosen, you could make a decision. For example, “disorganized” or “unreliable” seem like pretty career limiting vocabulary.

A similar concept could be applied to genetics. With the advent of faster and higher throughput sequencing technologies, it is now possible to genetically screen people for a number of diseases in a fraction of the time it used to take. This applies particularly to those diseases that are strongly related to having a mutation in a single gene, such as cystic fibrosis or Huntington’s disease (CFTR and huntingtin genes, respectively).

However, just like a single word can’t capture a person’s full personality, changes in a single gene are often insufficient for causing disease – many illnesses are influenced by multiple genes acting in concert. These diseases are far less easy to test for and to understand, because they are intrinsically harder to study.

For example, when a disease results from mutations in a single gene, this can be studied at the cellular level, using techniques like RNA interference or site-specific mutation to create cell lines that either don’t express a gene or express it in a mutated form. This, then, gives information about the role of the gene in normal physiology.

However, if a disease results from changes in two different genes, these laboratory techniques become far more difficult. And it’s even more challenging when three or four key genes are at play. So how could you study these conditions in an efficient manner?

Ideally, one would be able to turn off or mutate multiple genes at the flick of a switch. And while I’m perhaps being a little dramatic, that seems to be the promise of a new gene editing technology that has come out of Memorial Sloan Kettering Cancer Center.

In an article published in June’s Cell Stem Cell, the authors describe a technology they called iCRISPR. This system is based on two recent platforms for site-specific gene alteration, called TALEN and CRISPR. Individually, these techniques are impressive in that we have had the ability to introduce foreign genetic material into a genome for decades, but it is only recently that we can control exactly where in the genome it goes.

While somewhat of a simplification, these technologies require two basic components – 1) an enzyme to cut DNA 2) nucleic acids that target the enzyme to the region you want to mutate or delete.

The Huangfu lab brilliantly combines the two techniques – the TALEN system introduces the enzyme needed by the CRISPR system into a stable region of the genome in an induced pluripotent stem cell line (iPSC). Then, they can add multiple targeting nucleic acids into the mix, to affect multiple genes all at once – up to three genes in their studies. The enzyme that CRISPR needs to function is expressed under an inducible promoter, meaning that it will only be produced when the researchers add a certain chemical to the media, in this case doxycycline. In short, their platform is only active if they choose to “switch it on”.

It’s really quite brilliant. Creating iPSC lines with these features means that you can have an enormous supply of cells and can pre-differentiate them into whatever mature cell type you actually want to study. Then you can simultaneously knock out or alter your set of genes of interest, allowing you to investigate complex gene interactions in an efficient manner, at a point in development of your choosing.

Tweaking a small set of genes may still not capture 100% of the nature of a disease, but it may capture enough to significantly improve our understanding and modeling of it, leading to diagnostic and therapeutic advances. And the more people who are aware that technologies like this exist, the more interesting the questions we can ask and pursue.

Research Cited:
González F., Zhu Z., Zhong-Dong Shi, Katherine Lelli, Nipun Verma, Qing V. Li & Danwei Huangfu (2014). An iCRISPR Platform for Rapid, Multiplexable, and Inducible Genome Editing in Human Pluripotent Stem Cells, Cell Stem Cell, 15 (2) 215-226. DOI:
Joung J.K. (2012). TALENs: a widely applicable technology for targeted genome editing, Nature Reviews Molecular Cell Biology, 14 (1) 49-55. DOI:
Sander J.D. (2014). CRISPR-Cas systems for editing, regulating and targeting genomes, Nature Biotechnology, 32 (4) 347-355. DOI:

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Holly Wobma

Holly Wobma

MD/PhD student at Columbia University
Holly is an MD-PhD student at Columbia University in New York. She recently (2011) completed a Bachelor of Health Sciences Honours Degree from the University of Calgary, where she pursued research related to nanotechnology and regenerative medicine. In addition to research, she enjoys participating in science outreach roles. Previously, she contributed to an award-winning Nanoscience animation produced by the Science Alberta Foundation (“Do You Know What Nano Means?”), and served on the board of directors for the Canadian Institute for Photonic Innovations Student Network. Holly's lab tweets @GVNlab.
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2 Responses

  1. Feifan Zhang says:

    The iCRISPR paper published in Cell Stem Cell paper is not correctly cited. The authors should be González F., Zhu,Z., Zhong-Dong Shi, Katherine Lelli, Nipun Verma, Qing V. Li & Danwei Huangfu.

    • Lisa Willemse says:

      Hi Feifan and thanks for pointing out the error. We use a automatic citation generator and even though it lists the correct information, it appears that the code does not capture it correctly in this case. We’ve added the missing name.

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