Ferreting Out Genomic Secrets

Ferret

Ferret in a Colorado conservation center, U.S. Fish and Wildlife Service

Not only is the ferret (Mustela putorius furo) adept at navigating a dirt field or threading electrical cables through piping (in New Zealand, ferrets can be registered as electrician assistants), this furry 5-pounder ranks as a real heavyweight for studying respiratory diseases. In fact, much of our current thinking about influenza is influenced by research with ferrets.

Now, the ferret will stand out even more. As reported online in Nature Biotechnology, NIH-funded researchers recently sequenced the genome of the sable ferret, the type that is bred in the United States as a pet. By studying this genetic blueprint like an explorer would a map, scientists can perform experiments to learn more systematically how the ferret copes biologically with common or emerging respiratory pathogens, pointing the way to improved strategies to preserve the health and well being of humans and ferrets alike.

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Using Genomics to Follow the Path of Ebola

Ebola virus

Caption: Colorized scanning electron micrograph of filamentous Ebola virus particles (blue) budding from a chronically infected VERO E6 cell (yellow-green).
Credit: National Institute of Allergy and Infectious Diseases, NIH

Long before the current outbreak of Ebola Virus Disease (EVD) began in West Africa, NIH-funded scientists had begun collaborating with labs in Sierra Leone and Nigeria to analyze the genomes and develop diagnostic tests for the virus that caused Lassa fever, a deadly hemorrhagic disease related to EVD. But when the outbreak struck in February 2014, an international team led by NIH Director’s New Innovator Awardee Pardis Sabeti quickly switched gears to focus on Ebola.

In a study just out in the journal Science [1], this fast-acting team reported that it has sequenced the complete genetic blueprints, or genomes, of 99 Ebola virus samples obtained from 78 patients in Sierra Leone. This new genomic data has revealed clues about the origin and evolution of the Ebola virus, as well as provided insights that may aid in the development of better diagnostics and inform efforts to devise effective therapies and vaccines.

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Secrets of a Supercentenarian’s Genome

Hennie with her family

Caption: Hendrikje van Andel-Schipper (2nd from the left) in her youth. She was born June 29, 1890, premature and so tiny that no one thought she would survive. However, she lived to be 115.
Credit: Ramon Schipper

Not too long before 115-year-old Hendrikje “Hennie” van Andel-Schipper died in 2005, this Dutch “supercentenarian” attributed her remarkable longevity to eating raw salted herring, to drinking orange juice, and—with a twinkle in her eye—“to breathing.”

Because very few humans have survived as long Hennie, it’s only logical to ask whether some of the secrets to her impressive lifespan might lie in her genes. And we find ourselves in a great position to explore such questions, thanks to the convergence of two things: recent advances in DNA sequencing technology, and Hennie’s generous decision, made when she was a mere 82 years old, to donate her body to science upon her death.

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Happy Birthday, Jane Goodall!

Jane Goodall with Freud

Credit: Michael Neugebauer, courtesy of The Jane Goodall Institute
Caption: Dr. Jane Goodall with Freud, a Gombe chimpanzee

Today, I’d like to wish a very “Happy Birthday” to a dear friend and one of my personal heroes: Jane Goodall. Given Jane’s energy and youthful attitude, it’s hard to believe that this scientist who was so instrumental in advancing our understanding of primate behavior is turning 80 today.

But, indeed, more than a half-century has passed since Jane first traveled to Africa to begin her field research in Gombe National Park on the shores of Africa’s Lake Tanganyika. Her goal? To observe wild chimpanzees in their natural environment and analyze their behavior like no researcher had done before.

At first, the chimps were shy and ran away whenever Jane approached. But, as they grew used to the young biologist’s presence, they continued on with their daily activities as she carefully watched and meticulously recorded their actions, often equipped with nothing more than a pair of binoculars, a pencil, and a notebook. Her landmark work revealed that chimp behavior resembled human behavior in ways that no one had even imagined—findings that transformed our understanding of our closest relatives in the animal kingdom. Continue reading

Popular Genome Editing Tool Gets Its Close-Up

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!

References:

[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

Links:

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