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NIH Advances the Push for 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

Copy-Editing the Genome

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 manually 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 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 .
  • 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 .

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.

Reducing the Cost

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 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 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 . 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 , another team of researchers reported success in using two of these CRISPR/Cas RNAs to edit multiple sites simultaneously in a group of humancells—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.

Francis S. Collins, M.D., Ph.D. is the Director of the National Institutes of Health (NIH). In that role he oversees the work of the largest supporter of biomedical research in the world, spanning the spectrum from basic to clinical research. Dr. Collins is a physician-geneticist noted for his landmark discoveries of disease genes and his leadership of the international Human Genome Project, which culminated in April 2003 with the completion of a finished sequence of the human DNA instruction book. He served as director of the National Human Genome Research Institute at the NIH from 1993-2008.

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