Gene editing reverses Huntington's in mouse model

This is a concrete example, not yet clinical, of what can be done with CRISPR/Cas9 gene Read more

Urine tests for prostate cancer could reduce biopsies

Urine RNA tests could reduce the number of biopsies by giving a preview of a cancer's aggressiveness. Featuring Martin Sanda and Carlos Read more

Mitochondrial blindness -- Newman's Emory story

Neuro-ophthalmologist Nancy Newman’s 2017 Dean’s Distinguished Faculty Lecture and Award were unexpectedly timely. Her talk on Tuesday was a tour of her career and mitochondrial disorders affecting vision, culminating in a description of gene therapy clinical trials for the treatment of Leber’s hereditary optic neuropathy. The sponsor of those studies, Gensight Biologics, recently presented preliminary data on a previous study of their gene therapy at the American Academy of Neurology meeting in April. Two larger trials Read more

Heart

There will be microparticles (in stored blood)

More than 9 million people donate blood in the United States every year, according to the American Red Cross. Current guidelines say that blood can be stored for up to six weeks before use.

What happens to red blood cells while they are in storage, which transfusion experts call the “storage lesion”? Multiple studies have shown that older blood may have sub-optimal benefits for patients receiving a transfusion. The reasons include: depletion of the messenger molecule nitric oxide, lysis of red blood cells and alterations in the remaining cells’ stiffness.

To that list, we could add the accumulation of microparticles, tiny membrane-clothed bags that contain proteins and RNA, which have effects on blood vessels and the immune system upon transfusion. Note: microparticles are similar to exosomes but larger – the dividing line for size is about 100 nanometers. Both are much smaller than red blood cells.

EUH blood bank director John Roback recently gave a talk on the blood storage issue, and afterwards, cardiologist Charles Searles and research fellow Adam Mitchell were discussing their work on microparticles that come from red blood cells (RBCs). They have been examining the effects RBC-derived microparticles have on endothelial cells, which line blood vessels, and on immune cells’ stickiness.Red blood cell microparticles280

Mitchell mentioned that he had some striking electron microscope images of microparticles and some of the particles looked like worms. With the aim of maintaining Lab Land’s “Cool Image” feature, I resolved to obtain a few of his photos, and Mitchell generously provided several.

“Those worms definitely had me mesmerized for a while,” he says.

In his talk, Roback described some of the metabolomics research he has been pursuing with Dean Jones. Instead of focusing only on how long blood should be stored, Roback’s team is examining how much differences between donors may affect donated blood’s capacity to retain its freshness. Read more

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Decoding lupus using DNA clues

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

A team of Emory scientists has been investigating some fundamental questions about lupus: where do the cells that produce the self-reactive antibodies come from? Are they all the same?

In the accompanying video, Kelli Williams, who helps study the disease and has lupus herself, describes what a flare feels like. In addition, Emory researchers Iñaki Sanz, MD and Chris Tipton, PhD explain their findings, which were published this summer in Nature Immunology.

Judging by the number and breadth of abstracts on lupus at the Department of Medicine Research Day (where Tipton won 1st place for basic science poster), more intriguing findings are in the pipeline. Goofy Star Wars metaphors and more explanations of the science here.

Posted on by Quinn Eastman in Immunology Leave a comment

Islet transplants from fish?

The shortage of human organ donors has led scientists to investigate animals as a potential source for transplantable organs or tissues. Pigs are often mentioned because of their size: similar to ours.

Recently, prospects for xenotransplantation brightened when Harvard geneticist George Church demonstrated the removal of dozens of endogenous retroviruses from the pig genome, in a tour de force of the CRISPR/Cas9 gene editing technique.

Emory researchers Susan Safley and Collin Weber have been exploring the possibility of using different animals for xenotransplantation: fish, specifically tilapia.

Why fish? This review details several advantages tilapia may offer in the field of islet transplant, but first – a reminder about islets.

Islets are the clusters of cells in the pancreas that produce insulin. Several clinical trials, including this one led by Emory’s Nicole Turgeon, have shown that islets isolated from deceased human donors can restore normal blood sugar regulation in patients with type 1 diabetes. Still, obstacles remain such as the shortage of human islets, and the loss of insulin independence over time, even with the use of drugs that hold off immune rejection.

For islet transplant, here are some of the proposed advantages presented by tilapia:

*tilapia have large, distinct islet organs called Brockmann bodies that are easy to isolate

*tilapia grow quickly and cost less to raise than pigs

*tilapia islets are resistant to hypoxia, thought to contribute to graft loss

*tilapia do not express alpha (1,3) gal, a carbohydrate structure present on mammalian cells that causes hyperacute rejection Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Transformative awards for Mocarski’s malleable cells, lung fibrosis

The National Institutes of Health has announced a five-year, $1.9 million Transformative Research Award to Emory virologist Edward Mocarski, PhD for his work on how the mechanisms of programmed cell death can be subverted.

Mocarski is Robert W. Woodruff professor of microbiology and immunology at Emory University School of Medicine and Emory Vaccine Center. His research, which originated in probing how cells commit suicide when taken over by viruses, could lead to advances in regenerative medicine and organ transplant.

Barker Mocarski

Thomas Barker, PhD (left) and Edward Mocarski, PhD (right)

The grant, funded through the National Institute of Allergy and Infectious Diseases, is one of nine “high-risk-, high-reward” Transformative Research Awards (13 recipients) announced by the NIH on October 6.

In the same group this year, Thomas Barker in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University received a Transformative Research Award for his research on mechanosensors + pulmonary fibrosis.

The Transformative Research Award program supports “exceptionally innovative, unconventional, paradigm-shifting research projects that are inherently risky and untested.” Emory has achieved only one other TRA since the program was established in 2009: Shuming Nie’s project on imaging to guide cancer surgery. Read more

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Progress on universal flu vaccine

Flu viruses are constantly mutating and every year the seasonal flu shot is updated to keep up with the viruses that are making people sick. Readers interested in the prospect of a “universal flu vaccine” may have noticed some experimental progress on that theme this week.

The reports build on findings some years ago from Emory Vaccine Center researchers led by Rafi Ahmed. Ahmed’s team had showed that people infected by the 2009 H1N1 flu strain developed broadly protective antibodies, and separately, so did volunteers immunized against the H5N1 avian flu virus.

Some background: the head region of the flu virus’s mushroom-like hemagglutinin protein is more variable, and more exposed to the immune system, while the stem/stalk region is less variable.

The underlying idea is: if someone’s immune system is exposed to flu viruses different enough than what it has seen before (like in the 2009 H1N1 outbreak and the H5N1 study), the antibodies to the stem region become more important and more prominent.

The NIAID team fused the flu hemagglutinin to ferritin to make nanoparticles

The NIAID team fused the flu hemagglutinin to ferritin, a platform for further protein engineering.

This week, what the researchers from NIAID (Nature Medicine) and Scripps/J&J (Science) showed is that experimental vaccines made from the stem region only can be broadly protective in several animal models. This required some protein engineering and reconstruction because chopping off the head of the hemagglutinin protein makes it fall apart.

Emory Vaccine Center’s Walter Orenstein, in comments for Genetic Experts News Service, wrote:

These are animal studies, so we are some way off for development and testing of a vaccine in humans. The technique is promising and a step in the right direction. Read more

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Providing the potent part of probiotics

A Emory News item on a helpful part of the microbiome focuses on how the same type of bacteria – lactobacilli – activates the same ancient signaling pathway in intestinal cells in both insects and mammals. It continues a line of research from Rheinallt Jones and Andrew Neish on how beneficial bacteria stimulate wound healing by activating ROS (reactive oxygen species).

Asma Nusrat, MD

A idea behind this research is: if we know what parts of the bacteria stimulate healing, perhaps doctors can deliver that material, or something very close, to patients directly to treat intestinal diseases such as Crohn’s or ulcerative colitis.

This idea has advanced experimentally, as demonstrated by two papers from Jones and Neish’s frequent collaborator, Asma Nusrat, who recently moved from Emory to the University of Michigan. This team had shown that a protein produced by human intestinal cells called annexin A1 activates ROS, acting through the same N-formyl peptide receptors that bacteria do.

Nusrat told me Friday her team began investigating annexins a decade ago at Emory, and it was fortuitous that Neish was working on beneficial bacteria right down the hall, since it is now apparent that annexin A1 and the bacteria are activating the same molecular signals. (Did you know there is an entire conference devoted to annexins? I didn’t until a few days ago.)

In a second Journal of Clinical Investigation paper published this February, Nusrat and her colleagues show that intestinal cells release vesicles containing annexin A1 following injury. The wound closure-promoting effects of these vesicles can be mimicked with nanoparticles containing annexin A1. The nanoparticles incorporate a form of collagen, which targets them to injured intestinal tissue. Read more

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HIV vaccine news: a glass half full

This week, researchers from Yerkes and Emory Vaccine Center led by Cindy Derdeyn published a paper that I first thought was disturbing. It describes how monkeys vaccinated against HIV’s relative SIV (simian immunodeficiency virus) still become infected when challenged with the virus. Moreover, it’s not clear whether the vaccine-induced antibodies are exerting any selective pressure on the virus that gets through.

But then I realized that this might be an example of “burying the lead,” since we haven’t made a big hoopla about the underlying vaccine studies, conducted by Rama Amara. Some of these studies showed that a majority of monkeys can be protected from repeated viral challenge. The more effective vaccine regimens include adjuvants such as the immune-stimulating molecules GM-CSF or CD40L (links are the papers on the protective effects). Read more

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CMV reactivation warps immune system after HSCT

As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takes a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.

Leslie Kean, MD, PhD

The paper’s findings have implications for making this type of transplant safer and preventing graft-versus-host disease. In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a new one with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.

CMV is often thought of as harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new T cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which can compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients after kidney transplant.

The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010 (a host of Emory/Winship hematologists and immunologists are co-authors). This paper is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more

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Following lupus troublemaker cells, via DNA barcodes

People with systemic lupus erythematosus can experience a variety of symptoms, such as fatigue, joint pain, skin rashes and kidney problems. Often the symptoms come and go in episodes called flares. In lupus, the immune system goes haywire and produces antibodies that are directed against the body itself.

The immune system can produce many types of antibodies, directed against infectious viruses (good) or against human proteins as in lupus (harmful). Each antibody-secreting cell carries a DNA rearrangement that reflects the makeup of its antibody product. Scientists can use the DNA to identify and track that cell, like reading a bar code on an item in a supermarket.

SanzNew220

Iñaki Sanz, MD is a Georgia Research Alliance Eminent Scholar, director of the Lowance Center for Human Immunology and head of the Rheumatology division in the Department of Medicine.

Postdoc Chris Tipton, GRA Eminent Scholar Iñaki Sanz and colleagues at Emory have been using these DNA bar codes to investigate some fundamental questions about lupus: where do the autoantibody-producing cells come from? Are they all the same?

Their findings were published in Nature Immunology in May, and a News and Views commentary on the paper calls it “a quantum advance in the understanding of the origin of the autoreactive B cells.” It’s an example of how next-generation sequencing technology is deepening our understanding of autoimmune diseases.

The Emory team obtained blood samples from eight patients experiencing lupus flares and compared them to eight healthy people who had recently been vaccinated against influenza or tetanus.

When the immune system is responding to something it’s seen before, like when someone receives a booster vaccine, the bar codes of the antibody-producing cells look quite similar to each other. A set of just a few antibody-producing cells multiply and expand, making what looks like clones. In contrast, the researchers found that in lupus, many different cells are producing antibodies. Some of the expanded sets of cells are producing antibodies against infectious agents.

“We expected to see an expansion of the cells that produce autoantibodies, but instead we saw a very broad expansion of cells with all types of specificities,” Tipton says.

To use a Star Wars analogy: a booster vaccine response looks like the Clone Wars (oligoclonal — only a few kinds of monsters), but a lupus flare looks like a visit to Mos Eisley cantina (polyclonal — many monsters). Read more

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Subset of plasma cells display immune ‘historical record’

You may have read about recent research, published in Science, describing a technique for revealing which viruses have infected someone by scanning antiviral antibodies in the blood.

Emory immunologists have identified corresponding cells in which long-lived antibody production resides. A subset of plasma cells keep a catalog of how an adult’s immune system responded to infections decades ago, in childhood encounters with measles or mumps viruses.

The results, published Tuesday, July 14 in Immunity, could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

“If you’re developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen,” says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare’s Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Lee says that her team’s research on plasma cells in humans provided insights unavailable from mice, since mice don’t live as long and their plasma cells also have a different pattern of protein markers. More here.

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