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Manipulating Microbes: New Toolbox for Better Health?

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Bacteroides thetaiotaomicron

Caption: Bacteroides thetaiotaomicron (white) living on mammalian cells in the gut (large pink cells coated in microvilli) and being activated by exogenously added compounds (small green dots) to express specific genes, such as those encoding light-generating luciferase proteins (glowing bacteria).
Credit: Janet Iwasa, Broad Visualization Group, MIT Media Lab

When you think about the cells that make up your body, you probably think about the cells in your skin, blood, heart, and other tissues and organs. But the one-celled microbes that live in and on the human body actually outnumber your own cells by a factor of about 10 to 1. Such microbes are especially abundant in the human gut, where some of them play essential roles in digestion, metabolism, immunity, and maybe even your mood and mental health. You are not just an organism. You are a superorganism!

Now imagine for a moment if the microbes that live inside our guts could be engineered to keep tabs on our health, sounding the alarm if something goes wrong and perhaps even acting to fix the problem. Though that may sound like science fiction, an NIH-funded team from the Massachusetts Institute of Technology (MIT) in Cambridge, MA, is already working to realize this goal. Most recently, they’ve developed a toolbox of genetic parts that make it possible to program precisely one of the most common bacteria found in the human gut—an achievement that provides a foundation for engineering our collection of microbes, or microbiome, in ways that may treat or prevent disease.

Shattering News: How Chromothripsis Cured a Rare Disease

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Caption: Karyotype of a woman spontaneously cured of WHIM syndrome. These chromosome pairings, which are from her white blood cells, show a normal chromosome 2 on the left, and a truncated chromosome 2 on the right.
Source: National Institute of Allergy and Infectious Diseases , NIH

The world of biomedical research is filled with surprises. Here’s a remarkable one published recently in the journal Cell [1]. A child born in the 1950s with a rare genetic immunodeficiency syndrome amazingly cured herself years later when part of one of her chromosomes spontaneously shattered into 18 pieces during replication of a blood stem cell. The damaged chromosome randomly reassembled, sort of like piecing together a broken vase, but it was still missing a shard of 164 genes—including the very gene that caused her condition.

Researchers say the chromosomal shattering probably took place in a cell in the bone marrow. The stem cell, now without the disease-causing gene, repopulated her immune system with healthy bone marrow-derived immune cells, resulting in cure of the syndrome.

Popular Genome Editing Tool Gets Its Close-Up

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Swirls of blue with a gold and red DNA helix on top

Caption: Crystal structure of the Cas9 gene-editing enzyme (light blue) in complex with an RNA guide (red) and its target DNA (yellow).
Credit: Bang Wong, Broad Institute of Harvard and MIT, Cambridge, MA

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 [1].

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 [2].  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!


[1] 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.

[2] 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

Foundation for the NIH to Award Lurie Prize in Biomedical Sciences to Jennifer Doudna from UC Berkeley, 25 February 2014

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

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