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Copy-editing the Genome: Extreme Personalized Medicine?

COOL TOOL. See how the TALE protein (rainbow colored) recognizes the target DNA site and wraps around the double helix. When this TALE protein is fused to a nuclease (the scissors), creating a TALEN, the hybrid protein will clip the DNA at the target site. Credit: Jeffry D. Sander, Massachusetts General Hospital

If I made a spelling mistake in this blog, and you were my copy editor, you’d want to fix it quickly. You’d delete the wrong letter and insert the correct one. Well, DNA is a language too, with just four letters in its alphabet; and disease can occur with just one letter out of place if it’s in a vulnerable position (think sickle cell anemia or the premature aging disease, progeria). Wouldn’t it be great for tomorrow’s physicians to be able to do what the copy editor does? That is, if they could fix a genetic mutation quickly and efficiently, without messing up the rest of the text?

We hear the phrases “genetically modified” and “genetically engineered” everyday, which may lead you to think it’s simple to edit DNA surgically. But it’s not! So, whenever researchers create a new tool for precisely modifying DNA the way a copy editor does, it’s a big deal. Today, I’d like to give a shout out to a new generation of tools we’ll call copy-editing nucleases. These new tools, all of which were developed with the help of NIH funding, are making it faster, easier, and cheaper to edit DNA, and they’re revealing tantalizing new possibilities for treating human diseases.

To give you an idea of how challenging it is to edit DNA, consider this: the human genome has about 3 billion pairs of the chemical letters A, C, G, and T (adenine, cytosine, guanine, and thymine). Now, imagine how much work it would take to search a book with 3 billion letters for a single appearance of the word “CAT,” and then cut out a “C” and paste in a “T” to make the word “TAT.”

To meet this challenge, you would need an enzyme that is both capable of precise recognition of a specific DNA sequence and outfitted with scissors and paste to modify it. The simplest version is just to include the scissors, interrupting the targeted gene. Researchers [1] have developed editing tools called zinc finger nucleases (ZFNs), which are proteins specifically designed to grab onto a sequence of DNA and cut it.

Why would you do this? Well, you might want to find out what happens if you delete a gene from an organism’s genome. Or you might want to snip out one version of a gene and then, using another trick, replace it with a different segment to compare how different versions affect disease risk. For example, a team at The Whitehead Institute in Cambridge, MA, has used ZFNs to produce stem cells that carry one of two different genetic mutations known to increase the risk of early onset Parkinson’s disease [2].

Ultimately, you might want to replace a disease-causing mutation with a “healthy” snippet of DNA. In 2011, a team from Massachusetts General Hospital in Boston and Stanford University in Palo Alto, CA did just that. They used a specially engineered ZFN to correct the mutation that causes sickle cell anemia in induced pluripotent stem (iPS) cells derived from a patient with the disease [3].

This strategy could, someday, be used to generate genetically corrected, patient derived cells that could be transplanted without fear of rejection or the use of immunosuppressive drugs.

However, we still need better tools. ZFNs are tricky to engineer and can be quite expensive if purchased from a commercial source—about $6,000 each. The high cost and difficulty of working with ZFNs drove the discovery and development of new editing tools called transcription activator-like effector nucleases (TALENs) in 2009 [4] [5] and, most recently, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas nuclease systems. Despite their horribly complicated names, this next generation of seek-and-slice nucleases [6] is simpler to design and much cheaper to make, e.g., $150 for a pair of TALENs.

The CRISPR/Cas system is a little different, because rather than using a protein to find the desired DNA sequence, it uses RNA to guide the slicing enzyme to the target [7]. This takes advantage of the natural pairing of RNA and DNA sequences, using the matching properties that Watson and Crick figured out almost 60 years ago. RNA also happens to be cheaper to manufacture than a protein.

Just this month in the journal Science [8], another team of researchers reported success in using two of these CRISPR/Cas RNAs to edit multiple sites simultaneously in a group of human cells—an impressive achievement that’s been dubbed “multiplex editing.”

Still, a lot more research remains to be done before we can think about moving these copy-editing strategies out of the lab and into the clinic. One big unknown is whether these new tools have “off-target” effects. This issue is critical because while fixing a target gene, you don’t want to damage another gene important for health or development. And the genome is like a very big encyclopedia, so even a small risk of hitting the wrong word could be a problem.

What’s clear today is that these new DNA-editing tools are transformative technologies that are serving to accelerate biological science around the world. They’re enabling researchers to gain a better understanding of exactly how a gene, mutation, or simple variation, affects cell function and health. And, while the ability to manipulate the genome of any organism represents a leap forward in scientific knowledge, I expect that ultimately we will develop the ability to edit our own genome in safe, responsible ways that relieve human suffering and improve human health.



[1] Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Kim YG, Cha J, Chandrasegaran S. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):115660.

[2] Generation of isogenic pluripotent stem cells differing exclusively at two early onset Parkinson point mutations. Soldner F, Laganière J, Cheng AW, Hockemeyer D, Gao Q, Alagappan R, Khurana V, Golbe LI, Myers RH, Lindquist S, Zhang L, Guschin D, Fong LK, Vu BJ, Meng X, Urnov FD, Rebar EJ, Gregory PD, Zhang HS, Jaenisch R. Cell. 2011 Jul 22;146(2):318-31.

[3] In situ genetic correction of the sickle cell anemia mutation in human induced pluripotent stem cells using engineered zinc finger nucleases. Sebastiano V, Maeder ML, Angstman JF, Haddad B, Khayter C, Yeo DT, Goodwin MJ, Hawkins JS, Ramirez CL, Batista LF, Artandi SE, Wernig M, Joung JK. Stem Cells. 2011 Nov;29(11):1717-26.

[4] A simple cipher governs DNA recognition by TAL effectors. Moscou MJ, Bogdanove AJ. Science. 2009 Dec 11;326(5959):1501.

[5] Breaking the code of DNA binding specificity of TAL-type III effectors. Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, Lahaye T, Nickstadt A, Bonas U. Science. 2009 Dec 11;326(5959):1509-12.

[6] FLASH assembly of TALENs for high-throughput genome editing. Reyon D, Tsai SQ, Khayter C, Foden JA, Sander JD, Joung JK. Nat Biotechnol. 2012 May;30(5):460-5. 

[7] RNA-Guided Human Genome Engineering via Cas9. Mali P, Yang L, Esvelt KM, Aach J, Guell M, Dicarlo JE, Norville JE, Church GM. Science. 2013 Jan 3.

[8] Multiplex Genome Engineering Using CRISPR/Cas Systems. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Science. 2013 Jan 3.

8 comments to Copy-editing the Genome: Extreme Personalized Medicine?

  • Gary Temple

    This concise, plain-spoken summary of genetic editing has inspired me to use a similar approach for a brief presentation on genetic engineering to students in 7th grade genetics classes in which I am volunteering. Thank you.

    • Dr. Francis Collins

      Good to hear from you, Gary! It’s great to hear that you’re sharing your knowledge of science with 7th graders. I’d like to encourage more biomedical researchers to follow your lead and do whatever they can to encourage the next generation of scientists.

  • Alex Robertson

    Fascinating; thank you. Alex

  • Garland Eiland

    Dr. Collins,

    Do you believe it will one day be possible to use computational methods to predict the implications of using such a tool to edit portions of the genome? While this research is exciting, it is more complex than we currently can conceive. As you mentioned, editing the wrong area can have unknown consequences for other regions. Unless the experiments being carried out have readily measurable/recognized phenotypes, we will continue to ‘shoot in the dark’ for answers to this puzzle. We have to do more to understand what this information is and how all the integral pieces correlate, ultimately to function. I am familiar with your background as a physicist and as such, I must ask for your opinion. You have said that spending time in your data is like spending time in God’s word – not an exact quote but what I heard from a Stanford visit. You see things there, differently from others. I would appreciate knowing more about your thoughts in how best to approach interpreting this exciting information we now have. I believe we are in a new era of science, in terms of technology and what information we have – but we struggle with how to interpret it. What experiments to do, what are the right questions to be asking? We seem to circle, chasing our tails a lot – asking the wrong questions. You are in a position to help guide us and you have great faith that we will succeed in helping patients fight disease – your blog is testimony to that. Where do you see us now? In terms of using what you helped uncover for us, how are we doing? What can we do to speed things up a bit?

  • annie achee

    Will this or can this be applied to rare cancers such as leiomyosarcomas? Can tumor tissue samples be used for such research? … Please let me know. thank you so much.

    • Hi, Annie! Thanks for your thoughtful questions. While one never knows what the future may hold, we aren’t aware of any immediate applications of DNA copy-editing technologies to cancer or to tumor tissue samples.

      Right now, most DNA copy-editing research is focused on developing ways to treat conditions caused by a mutation in a single gene, such as sickle cell disease. Researchers are also using these new technologies to create animal and/or cell-based models of conditions in which one or two genes are suspected of playing a major role in disease risk or onset, such as the early-onset Parkinson’s disease. We expect that such models will be valuable for improving our understanding of these diseases, as well as for testing new treatment strategies.

  • Jonathan

    Thank you for the update. I am curious, are DNA copy-editing methods specific to point mutations, or would they also be potentially applicable to editing copy-number variation?

    For example, could such methods be used to reduce the number of triplet repeats in genes where extra repeats are pathogenic? Alternatively, could such methods be used as way of altering telomere length through repeat insertion?

    • Moderator
      February 1, 2013 at 12:03 pm · Reply · Edit
      These are fascinating questions, Jonathan. However, the information needed to answer them appears to be a bit beyond what has been published to date. Perhaps you could pose your questions to the authors of the recent Science papers on CRISPR/Cas systems, cited in References 7 and 8 of this blog post.

      Good luck in your quest. And keep on asking those tough questions because that’s what science is all about!

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