The potential of a gene-silencing technique called RNA interference has long enticed biotechnology researchers. It’s used routinely in the laboratory to shut down specific genes in cells. Still, the challenge of delivery has held back RNA-based drugs in treating human disease.
RNA is unstable and cumbersome, and just getting it into the body without having it break down is difficult. One that hurdle is met, there is another: the vast majority of the drug is taken up by the liver. Many current RNA-based approaches turn this apparent bug into a strength, because they seek to treat liver diseases. See these articles in The Scientist and in Technology Review for more.
But what if you need to deliver RNA somewhere besides the liver?
Biomedical engineer Hanjoong Jo’s lab at Emory/Georgia Tech, working with Katherine Ferrara’s group at UC Davis, has developed technology to broaden the liver-dominant properties of RNA-based drugs.
Hanjoong Jo, PhD
The results were recently published in ACS Nano. The researchers show they can selectively target an anti-microRNA agent to inflamed blood vessels in mice while avoiding other tissues.
“We have solved a major obstacle of using anti-miRNA as a therapeutic by being able to do a targeted delivery to only inflamed endothelial cells while all other tissues examined, including liver, lung, kidney, blood cells, spleen, etc showed no detectable side-effects,” Jo says. Read more
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, 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
Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.
Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.
The results were published Tuesday, August 25 in PLOS Genetics.
“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.
Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.
Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?
The answer: a mutation appears in the RNA first. Read more
Emory is preparing to launch a center devoted to antibiotic resistance. On Wednesday, Arjun Srinivasan, one of the CDC’s point people for antibiotic use and hospital acquired infections, kicked off the preparations with a talk on the multifaceted nature of this problem.
Without attempting to cover everything related to antibiotic resistance (that would take a book — or several), I will note in an upcoming post how Emory and partners such as Children’s Healthcare of Atlanta already have begun assembling many of the necessary tools.
Tackling antibiotic resistance has to take into account the habits of physicians, the expectations of patient, improved surveillance and antibiotic overuse in agriculture, as well as research on new antibiotics and detecting dangerous bacteria. In short, it’s both a science and policy issue — captured well by the documentary Resistance.
At the end of his talk, Srinivasan made a remark that brought this home for me, saying “We just have to push all the boulders up the hill at the same time” in response to a question about balancing effort on science vs policy. Allusions to Sisyphus!
Yet he provided some hope too, highlighting a recent CDC study that models how a coordinated response to antibiotic resistance in health care facilities could substantially cut infections. Read more
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
Last week on Friday, Lab Land attended the annual Regenerative Engineering & Medicine center get-together to hear about progress in this exciting area.
During his talk, Tony Kim of Georgia Tech mentioned a topic that Rose Eveleth recently explored in The Atlantic: why aren’t doctors using amazing “nanorobots” yet? Or as Kim put it, citing a recent review, “So many papers and so few drugs.”
[A summary: scaling up is difficult, testing pharmacokinetics, toxicity and efficacy is difficult, and so is satisfying the FDA.]
The talks Friday emerged from REM seed grants; many paired an Emory medical researcher with a Georgia Tech biomedical engineer. All of these projects take on challenges in delivering regenerative therapies: getting cells or engineered particles to the right place in the body.
For example, cardiologist W. Robert Taylor discussed the hurdles his team had encountered in scaling up his cells-in-capsules therapies for cardiovascular diseases to pigs, in collaboration with Luke Brewster. The pre-pig phase of this research is discussed in more detail here and here. Read more
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
A paper from cardiologist Aloke Finn and colleagues (published Wednesday, Aug. 5 in Nature Communications) describes how the protein CD163, produced by macrophages, puts the brakes on muscle repair after ischemic injury in mice. Here’s why we think this paper is interesting.
*Speculatively, there are connections to the recent wave of “young blood cures old body” parabiosis research. Increased CD163 is a marker of aging in humans. Maybe low levels of CD163 are part of how young blood is restorative.
*Translational potential — it wouldn’t be too hard to make an antibody against human CD163. Something that blocks CD163 could possibly be used to treat muscle breakdown, which occurs in response to injury, inactivity and in diseases such as cancer and diabetes.
*Finn says his team was surprised to find that mice lacking CD163, tested in experiments where blood flow is restricted in one leg, showed increased blood vessel and muscle growth in the other leg. It looks like part of CD163’s role is to limit muscle regeneration to the site of injury. Read more
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