Posted on by Dr. Francis Collins
Now that we are in the “dog days” of summer, it’s time again to consider which books to pack (or load onto your e-reader) for your well-deserved getaway to the beach and beyond. With so many interesting titles published every year, it’s never easy to make recommendations. But I thought it might be fun to ask a few distinguished researchers to share a few of their favorite reads—both about science and other things in the world at large. Some might be classics; some might have just been published. It’s up to the guests to decide.
During the month of August, the NIH Director’s Blog will run a series of guest posts in which some of biomedical science’s most creative minds discuss one or two of the books they’ve been reading. I’m sure what they share will be informative, provocative, and possibly even provide you with a few more possibilities for your late summer reading list. So, please check out the blog next Tuesday for the first installment in our scientists’ summer reading series, which happens to be penned by an avid reader who also holds a Nobel Prize in Physiology or Medicine. Can anyone guess who it is?
Posted on by Dr. Francis Collins
If you’re not watching recent work in biology, you might have thought that light microscopy hit its limits years ago. After all, it’s been around a long time. But to the contrary, microscopic imaging technology just keeps getting better and better. Here you can look with unprecedented clarity at just one of the many dynamic processes going on within a living cell. Specifically, this video shows actin fibers (orange-red), which are key components of the cell’s cytoskeleton, slowly pulling clathrin-coated pits (green), which are basket-like structures containing molecular cargo, away from the cell’s external membrane and deeper within the cell.
This remarkable live-action view was produced using one of two new forms of extended-resolution, structured illumination microscopy (SIM). SIM is faster than other forms of super-resolution fluorescence microscopy. It’s also less damaging to cells, making it the go-to method for live-cell imaging. The downside has been SIM’s limited resolution—just twice that of conventional light microscopes. However, Nobel Prize-winner Eric Betzig and postdoc Dong Li of Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, along with colleagues including Jordan Beach and John Hammer at NIH’s National Heart, Lung, and Blood Institute, recently came up with two different solutions to enhance SIM’s spatial resolution.
Posted on by Dr. Francis Collins
Exactly one hundred years ago, Max von Laue won the Nobel Prize in Physics for discovering that when a crystal is bombarded with X-rays, the beams bounce off the electrons surrounding the nucleus of each atom and scatter, interfering with each other (like ripples in a pond) and creating a unique pattern. These diffraction patterns could be used to decipher the arrangement of atoms in the crystal. Since then, X-ray crystallography has been used to chart a vast number of biological structures, including those of DNA, proteins, and even whole viruses.
Now, NIH-funded researchers at the Broad Institute of MIT and Harvard (Cambridge, MA) have teamed up with researchers at the University of Tokyo (Japan) to use crystallography to generate a high-definition map of an innovative tool for editing genomes. Their image reveals the structure of Cas9—an enzyme with an amazing ability to slice DNA with exquisite precision—in complex with a molecule of RNA that is guiding it to a targeted region of DNA .
The Cas9 enzyme was originally discovered in bacteria. It’s a key part of an ancient microbial immune system, called CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats-Cas), that researchers recently discovered could be put to use as a tool for precisely altering DNA. This extraordinary system has been used to knock out genes in cells from bacteria, mice, and humans, and even to engineer monkeys with specific mutations that could serve as more accurate models of human disease.
Still, there’s room for improvement. Because Cas9 is rather large, Broad researcher Feng Zhang (a recipient of both the NIH Director’s Transformative Research Award and an NIH Director’s Pioneer Award) wants to trim the enzyme a bit so it could be packaged into viruses for new applications. Armed with the new crystal structure, Zhang’s team can now determine which regions of the enzyme are essential for editing DNA and which parts might be dispensable.
Another issue with Cas9 is that it occasionally makes errors, cutting the wrong region of DNA. Zhang thinks the new structural schematic of Cas9, along with the guide molecule RNA and target DNA, might point to ways in which the enzyme can be optimized to reduce the chance of errors.
Zhang’s team isn’t the only one interested in tweaking Cas9 to improve its engineering potential. A group led by Jennifer Doudna and Eva Nogales, both of the University of California, Berkeley, also recently used X-ray crystallography to generate images of two different versions of Cas9: one from Streptococcus pyogenes and the other from Actinomyces naeslundii . By the way, the Foundation for the NIH recently named Doudna as the winner of its 2014 Lurie Prize in the Biomedical Sciences. The NIH grantee received the award for her pioneering role in the 2012 discovery of the CRISPR gene-editing technique.
Thanks to all of these new crystal structures, the scientific community is a step closer to realizing the full potential of Cas9/CRISPR technology to advance our understanding of disease and accelerate development of treatments and cures. So, here’s to our old friend crystallography and all of the exciting ways in which it will continue to expand our scientific horizons for years to come!
 Crystal Structure of Cas9 in Complex with Guide RNA and Target DNA. Nishimasu H, Ran FA, Hsu PD, Konermann S, Shehata SI, Dohmae N, Ishitani R, Zhang F, Nureki O. Cell. 2014 Feb 12. pii: S0092-8674(14)00156-1.
 Structures of Cas9 Endonucleases Reveal RNA-Mediated Conformational Activation. Jinek M, Jiang F, Taylor DW, Sternberg SH, Kaya E, Ma E, Anders C, Hauer M, Zhou K, Lin S, Kaplan M, Iavarone AT, Charpentier E, Nogales E, Doudna JA. Science. 2014 Feb 6
Zhang Lab, Broad Institute of Harvard and MIT, Cambridge, MA
Genome Engineering Resource Center maintained by the Zhang Lab
Nureki Lab, Department of Biophysics and Biochemistry, The University of Tokyo
Doudna Lab, University of California, Berkeley, CA
The Nogales Lab, University of California, Berkeley, CA
NIH Director’s Pioneer Award. (NIH Common Fund)
NIH Director’s Transformative Research Award. (NIH Common Fund)
NIH support: Office of the Director (Common Fund); National Institute of Mental Health; National Institute of General Medical Sciences