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How CMV gets around

Human cytomegalovirus infects most people in the United States by the time they are 40 years old. HCMV is usually harmless in children and adults, but when pregnant women are infected for the first time, the infection can lead to hearing, vision or other problems in their babies once they are born. [It is also a problem for organ transplant recipients.] According to the Centers for Disease Control and Prevention, HCMV is usually transmitted by sexual contact, diapers or toys. Notably absent are references to needles. That means scientists who study how mouse CMV infection takes place by injecting the virus into the animal’s body are missing a critical step.

Postdoc Lisa Daley-Bauer, working with CMV expert Ed Mocarski, has a recent paper in the journal Cell Host & Microbe illuminating how the virus travels from sites of initial infections to the rest of the body. Defining the cells the virus uses to get around could have implications for efforts to design a HCMV vaccine.

The virus hijacks part of the immune system, the authors find. CMV emits its own attractant (or chemokine) for patrolling monocytes, a type of white blood cell that circulates in the skin and peripheral tissues. This attractant, called MCK2, is only important when mice are infected by footpad inoculation, not by systemic injection.

Posted on by Quinn Eastman in Immunology Leave a comment

Fluorescent jungle gyms made of DNA

The 1966 movie “Fantastic Voyage” presented a vision of the future that includes tiny machines gliding through the body and repairing injuries. Almost 50 years later, scientists are figuring out how to form building blocks for such machines from DNA.

A new paper in Science describes DNA-based polyhedral shapes that are larger and stronger than scientists have built before. Right now, these are just static shapes. But they provide the scaffolding on which scientists could build robot walkers, or cages with doors that open and close. Already, researchers are talking about how such structures could be used to deliver drugs precisely to particular cells or locations in the body.

“Currently DNA self-assembly is perhaps one of the most promising methods for making those nanoscale machines,” says co-author Yonggang Ke, PhD, who recently joined the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University as assistant professor.

The research team was led by Peng Yin, PhD at Harvard’s Wyss Institute for Biologically Inspired Engineering. Working with the same team, Ke was also first author on a 2012 paper in Science describing “DNA bricks” resembling LEGO® blocks.

In the current paper, the shapes are made up of strut-reinforced tripods, which assemble themselves from individual DNA strands in a process called “DNA origami.” Already, at 5 megadaltons, each tripod is more massive than the largest known single protein (titin, involved in muscle contraction) and more massive than a ribosome, one of the cellular factories in which proteins are made. The tripods in turn can form prism-like structures, 100 nanometers on each side, that begin to approach the size of cellular organelles such as mitochondria.

The prism structures are still too small to see with light microscopes. Because electron microscopy requires objects to be dried and flattened, the researchers used a fluorescence-based imaging technique called “DNA PAINT” to visualize the jungle-gym-like structures in solution.

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DNA is not necessarily the most durable material for building a tiny machine. It is vulnerable to chemical attack, and enzymes inside the body readily chew up DNA, especially exposed ends. However, DNA presents some advantages: it’s easy (and cheap) to synthesize in the laboratory, and DNA base-pairing is selective. In fact, says Ke, these intricate structures assemble themselves: put all the components together in one tube, and all the DNA sequences that are supposed to pair up find each other.DNA polyhedra

Each leg of the tripod is made of 16 DNA double helices, connected together in ways that constrain the structure and make it stiff. The tripods have “sticky ends” that are selective and can assemble into the larger pyramids or prism structures. Previous efforts to build polyhedral structures were like trying to make a jungle gym out of rope: they were too floppy and hard to assemble.

To see the pyramid and prism structures, the research team used the “DNA-PAINT” technique, which uses fluorescent DNA probes that transiently bind to the DNA structures. This method enables visualization of structures that cannot be seen with a conventional light microscope. Why not simply make the DNA structures themselves fluorescent? Because shining strong light on such structures would quickly quench their fluorescence signal.

In his own work in Atlanta, Ke says he plans to further customize the DNA structures, combining the DNA with additional chemistry to add other functional molecules, including proteins or nanoparticles. He is especially interested in developing DNA-based materials that can manipulate or respond to light or carry magnets, with potential biomedical applications such as MRI imaging or targeted drug delivery.

Posted on by Quinn Eastman in Uncategorized Leave a comment

Hypersomnia update: beyond subject one

It’s not sleep apnea. It’s not narcolepsy. Hypersomnia is a different kind of sleep disorder. There’s even an “apples and oranges” T-shirt (see below) that makes that point.

This weekend, your correspondent attended a patient-organized Living with Hypersomnia conference. One of the main purposes of the conference was to update sufferers and supporters on the state of research at Emory and elsewhere, but there was also a lot of community building – hence the T-shirts.

The story of how sleep took over one young lawyer’s life, and how her life was then transformed by flumazenil, a scarce antidote to sleeping pills she was not taking, has received plenty of attention.

Now an increasing number of people are emerging who have a condition similar to Anna Sumner’s, and several questions need answers. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

NMDA receptors: triple-quadruple axel

NMDA receptors are saddled with an unwieldy name, but they are some of the most important* signaling molecules in the brain, both for learning and memory and in neurological and psychiatric diseases.

Kasper Hansen, a postdoc from Stephen Traynelis’ lab who is establishing his own at the University of Montana, is lead author on a recent paper in Neuron, which could spur research on NMDA receptors’ pharmacological properties.

The NMDA receptors in the brain are actually mix-and-match assemblies of four subunits, and most of the time in the brain, three different proteins come together to make one receptor, the authors explain. In the laboratory, it has been easier to study simpler, more homogenous, but also more artificial constructs. Hansen and his colleagues developed a way to build replicas of the more complicated NMDA receptors found in the brain and probe their distinct responses to drugs. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Two heavy hitters in this week’s Nature

Two feature articles in Nature this week on work by Emory scientists.

One is from Virginia Hughes (Phenomena/SFARI/MATTER), delving into Kerry Ressler’s and Brian Dias’ surprising discovery in mice that sensitivity to a smell can be inherited, apparently epigenetically. Coincidentally, Ressler will be giving next week’s Dean’s Distinguished Faculty lecture (March 12, 5:30 pm at the School of Medicine).

Another is from Seattle global health writer Tom Paulson, on immunologist Bali Pulendran and using systems biology to unlock new insights into vaccine design.

Posted on by Quinn Eastman in Immunology, Neuro Leave a comment

Personalized molecular medicine part 3

This is a continuation of previous posts on individualized treatment for infantile-onset epilepsy, made possible by Emory scientists Stephen Traynelis and Hongjie Yuan’s collaboration with the NIH Undiagnosed Diseases Program. A companion paper containing some clinical details was recently published in Annals of Clinical and Translational Neurology.

Memantine, which was found to be effective for this particular child, is normally used to treat symptoms of Alzheimer’s disease. He has a mutation in a gene encoding a NMDA receptor, an important signaling molecule in the brain, which hyperactivates the receptor. Treatment with memantine reduced his seizure frequency from 11 per week to three per week, and eliminated one type of seizure, myoclonic jerks. It allowed doctors to taper off conventional anticonvulsant drugs, which were having little effect anyway. His cognitive ability has remained unchanged.

The team also discovered that the compound dextromethorphan, found in many over-the-counter cough medicines, was effective in the laboratory in counteracting the effects of a GRIN2A mutation found in another patient. However, these effects were mutually exclusive, because the molecular effects of the mutations are different; memantine helps L812M, while dextromethorphan helps N615K.

Yuan and Traynelis report they have an ongoing collaboration with UDP investigators to analyze the effects of mutations in NMDA receptor genes. That means more intriguing case reports are coming, they say.

Tyler Pierson, MD, PhD, lead author of the clinical paper who is now at Cedars-Sinai Medical Center in Los Angeles, and David Adams, MD, PhD, senior staff clinician at NIH, provided some additional information on the patient in the study, shown here in a Q + A format. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Personalized molecular medicine part 2

This is a continuation of the post from last week on the early-onset epilepsy patient, whom doctors were able to devise an individualized treatment for. The treatment was based on Emory research on the molecular effects of a mutation in the patient’s GRIN2A gene, discovered through whole exome sequencing.*

For this patient, investigators were able to find the cause for a previously difficult to diagnose case, and then use a medication usually used for Alzheimer’s disease (memantine) to reduce his seizure frequency.

Last week, I posed the question: how often do we move from a disease-causing mutation to tailored treatment? Read more

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment

Souped-up method for iPS cell reprogramming

Peng Jin and collaborators led by Da-Hua Chen from the Institute of Zoology, Chinese Academy of Sciences have a new paper in Stem Cell Reports. They describe a souped-up method for producing iPS cells (induced pluripotent stem cells).

Production of iPS cells in the laboratory is becoming more widespread. Many investigators, including those at Emory, are using the technology to establish “disease in a dish” models and derive iPS cells from patient donations, turning them into tools for personalized medicine research.

Read more

Posted on by Quinn Eastman in Cancer, Immunology, Neuro Leave a comment

True personalized medicine: from mutation to treatment

Stephen Traynelis and Hongjie Yuan

Stephen Traynelis, PhD and Hongjie Yuan, MD, PhD

How often can doctors go from encountering a patient with a mysterious disease, to finding a mutation in a gene that causes that disease, to developing a treatment crafted for that mutation?

This is true personalized molecular medicine, but it’s quite rare.

How rare this is, I’d like to explore more, but first I should explain the basics.

At Emory, Stephen Traynelis and Hongjie Yuan have been working with Tyler Pierson, David Adams, William Gahl, Cornelius Boerkoel and doctors at the National Institutes of Health’s Undiagnosed Diseases Program (UDP) to investigate the effects of mutations in the GRIN2A gene.

Their report on the molecular effects of one such mutation, which caused early-onset epilepsy and intractable seizures in a UDP patient, was recently published in Nature Communications.

With that information in hand, UDP investigators were able to repurpose an Alzheimer’s medication as an anticonvulsant that was effective in reducing seizure frequency in that patient. [The details on that are still unpublished but coming soon.]

Read more

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Local events: complex neuro diseases, DNA repair

Just a note for Atlanta-area readers about two interesting lecture series.

One is the Suddath Symposium, a two-day event today and Friday at Georgia Tech focusing on DNA repair in human disease. This is an area that Emory is strong in: Gray Crouse, Paul Doetsch, Willian Dynan and Gang Bao are speaking (all on Friday).

Another is a series of talks from Emory investigators on complex neurological diseases, being put on by the Department of Cell Biology. Four, one a week (originally), all on Wednesdays at 4 pm in Whitehead 400.

Yesterday: Peter Wenner (homeostatic mechanisms/scaling). Feb. 26: Shannon Gourley (stress hormones/distorted decision-making/depression). March 5: Andrew Escayg (sodium channels/inherited epilepsy). Kerry Ressler (fear learning/PTSD) was supposed to be last week but that was derailed by ice. So Ressler will speak  on May 21, according to organizer Victor Faundez, who chose Picasso’s Guernica as the visual theme.

 

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment
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