About one third of people with depression have high levels of inflammation markers in their blood. New research indicates that persistent inflammation affects the brain in ways that are connected with stubborn symptoms of depression, such as anhedonia, the inability to experience pleasure.
The results were published online on Nov. 10 inÂ Molecular Psychiatry.
The findings bolster the case that the high-inflammation form of depression is distinct, and are guiding researchersâ€™ plans to test treatments tailored for it.
Anhedonia is a core symptom of depression that is particularly difficult to treat, says lead author Jennifer Felger, PhD, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine and Winship Cancer Institute.
“Some patients taking antidepressants continue to suffer from anhedonia,” Felger says. “Our data suggest that by blocking inflammation or its effects on the brain, we may be able to reverse anhedonia and help depressed individuals who fail to respond to antidepressants.”
In a study of 48 patients with depression, high levels of the inflammatory marker CRP (C-reactive protein) were linked with a “failure to communicate”, seen through brain imaging, between regions of the brain important for motivation and reward.
Emory researchers have found that high inflammation in depression is linked to a “failure to communicate” between two parts of the brain: the ventral striatum (VS, vertical cross section) and the ventromedial prefrontal cortex (vmPFC, horizontal). Images from Felger et al, Molecular Psychiatry (2015).
Neuroscientists can infer that two regions of the brain talk to each other by watching whether they light up in magnetic resonance imaging at the same times or in the same patterns, even when someone is not doing anything in particular. They describe this as “functional connectivity.”
In the field of cell therapy for cardiovascular diseases, researchers see two main ways that the cells can provide benefits:
*As building blocks â€“ actually replacing dead cells in damaged tissues
*As nurses — supplying growth factors and other supportive signals, but not becoming part of damaged tissues
Tension between these two roles arises partly from the source of the cells.
Many clinical trials have used bone marrow-derived cells, and the benefits here appear to come mostly from the â€œparacrine” nurse function.Â A more ambitious approach is to use progenitor-type cells, which may have to come from iPS cells or cardiac stem cells isolated via biopsy-like procedures. These cells may have a better chance of actually becoming part of the damaged tissueâ€™s muscles or blood vessels, but they are more difficult to obtain and engineer.
A related concern: available evidence suggests introduced cells â€“ no matter if they are primarily serving as nurses or building blocks — donâ€™t survive or even stay in their target tissue for long.
Transplanted cells were labeled with a red dye, while a perfused green dye shows the extent of functional blood vessels. Blue is DAPI, staining nuclear DNA. Yellow arrows indicate where red cells appear to contribute to green blood vessels. Courtesy of Sangho Lee.
Stem cell biologist Young-sup Yoon and colleagues recently published a paper in Biomaterials in which the authors use chitosan, a gel-like carbohydrate material obtainedÂ by processing crustacean shells, to aid in cell retention and survival. Ravi Bellamkonda’s lab at Georgia Tech contributed to theÂ paper.
More refinement of these approaches are necessary before clinical use, Â but it illustrates how engineered mixtures of progenitor cells and supportive materials are becoming increasingly sophisticated and complicated.
The chitosan gelÂ resemblesÂ the alginate material used to encapsulate cellsÂ by the Taylor lab.Â Yoon’s teamÂ wasÂ testing efficacy in a hindlimb ischemia model, in which a mouseâ€™s leg is deprived of blood. This situation is analogous to peripheral artery disease, and the readout of success is the ability of experimental treatments to regrow capillaries in the damaged leg.
The current paper builds a bridge between the nurse and building block approaches, because the researchers mix two complementary types of cells: an angiogenic one derived from bone marrow cells that expands existing blood vessels, and a vasculogenic one derived from embryonic stem cells that drives formation of new blood vessels.Â Note: embryonic stem cells were of mouse origin, not human. Read more
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.
Thomas Barker, PhD (left) and Edward Mocarski, PhD (right)
The grant, funded through the National Institute of Allergy and Infectious Diseases, is one of nineÂ â€œhigh-risk-, high-rewardâ€ 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 atÂ Georgia Tech and Emory University received a Transformative Research AwardÂ for his research on mechanosensors + pulmonary fibrosis.
TheÂ Transformative Research Award programÂ supports â€œexceptionally innovative, unconventional, paradigm-shifting research projects that are inherently risky and untested.â€ Emory has achieved only one other TRA since the program was established in 2009: Shuming Nie’s project onÂ imaging to guide cancer surgery. Read more
The potential of a gene-silencing technique called RNA interference has long enticedÂ biotechnology researchers. Itâ€™s used routinelyÂ in the laboratory to shut down specific genes in cells. Still, the challenge of delivery has held back RNA-based drugsÂ inÂ 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 upÂ by the liver. Many current RNA-based approaches turnÂ 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 Joâ€™s lab at Emory/Georgia Tech, working with Katherine Ferraraâ€™s group at UC Davis, has developed technologyÂ to broadenÂ the liver-dominantÂ 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-microRNAÂ agent to inflamed blood vessels in mice while avoiding other tissues.
â€œWe 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,â€ Jo says. 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 arenâ€™t doctors using amazing â€œnanorobotsâ€ yet? Or as Kim put it, citing a recent review, â€œSo many papers and so few drugs.â€
[A summary: scaling up is difficult, testing pharmacokinetics, toxicity and efficacy is difficult, and so is satisfying the FDA.]
TheÂ talks Friday emerged from REM seed grants; manyÂ 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
Please welcome stem cell/cardiology researcher Hee Cheol Cho to Emory. Starting in September, Cho joined the Wallace H Counter Department of Biomedical Engineering at Georgia Tech and Emory, and Emory-Children’s Pediatric Research Center. He and his team will focus on developing gene-and cell-based therapies for cardiac arrhythmias. Their research will adding to and complement the research of several groups, such as those led by Chunhui Xu, Young-sup Yoon, Mike Davis and W. Robert Taylor.
Cho comes from Cedars-Sinai Medical Center in Los Angeles, where he specialized in understanding cardiac pacemaker cells, a small group of muscle cells in the sinoatrial node of the heart that initiate cardiac contraction. These cells have specialized electrophysiological properties, and much has been learned in the last few years about the genes that control their development.
Cho and colleagues from Cedars-Sinai recently published a paper in Stem Cell Reports describing how the gene SHOX2 can nudge embryonic stem cells into becoming cardiac pacemaker cells. Read more
Cardiologist Bob Taylor and colleagues have a new paper in PLOS One this week, looking at the biomechanical forces behind plaque erosion.
Plaque erosion is a mechanism for blood clots formation in coronary arteries that is not as well-understood as its more explosive counterpart, plaque rupture. Plaque erosion disproportionally affects women more than men and is thought to account for most heart attacks in younger womenÂ (women younger than 50).
â€œWe believe that this work has implications for our better understanding of the underlying biology of coronary artery disease in women,â€ Taylor says. The first author of the paper isÂ biomedical engineering graduate student Ian Campbell, who now has his PhD. The team collaborated with cardiovascular pathologist Renu Virmani in Maryland.
Cardiologists have well-developedÂ ideas for how plaque rupture works*; see the concept of â€œvulnerable plaque.â€ Cholesterol and inflammatory cells build up in the coronary arteries over several years. At one point in a particular artery, the plaque has a core of dying inflammatory cells, covered by a fibrous cap. If the cap is thin (the patterns of blood flows near the cap influence this), there is a risk that the cap will break and the contents of the core will spill out, triggering a blood clot nearby.
Plaque erosion is more mysterious and can occur more gradually, the researchers have found. Read more
DNA bricks keep getting larger. In 2012, a team of researchers at Harvard described their ability to make self-assembling structures –made completely out of DNA — that were about the size of viruses (80 nanometers across).
Yonggang Ke, PhD
Now theyâ€™re scaling up, making bricks that are 1000 times larger and getting close to a size that could be barely visible to the naked eye.
The advances were reported in Nature Chemistry.
Who: a team of researchers at the Wyss Institute at Harvard led by Peng Yin, and including Yonggang Ke, PhD, now an assistant professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.
At Emory, Ke and his team are continuing to design 3D DNA machines, withÂ potential functionsÂ such as fluorescent nanoantennae, drug delivery vehicles and synthetic membrane channels.
How: The DNA brick method uses short, synthetic strands of DNA that work like interlocking LegoÂ® bricks to build complex structures. Structures are first designed using a computer model of a molecular cube, which becomes a master canvas. Each brick is added or removed independently from the 3D master canvas to arrive at the desired shape. TheÂ DNA strands that would match up to achieve the desired structure are mixed together and self assemble — with the help of magnesium salts — to achieve the designed crystal structures.
“Therein lies the key distinguishing feature of our design strategyâ€“its modularity,” Ke says. “The ability to simply add or remove pieces from the master canvas makes it easy to create virtually any design.”
What for: AsÂ part of this study the team demonstrated the ability to position gold nanoparticles less than two nanometers apart from each other along the crystal structure â€” a critical feature for future quantum computational devices and a significant technical advance for their scalable production.
Biomedical engineer Yonggang Ke‘s “DNA origami” artwork appears on the cover of Nature Methods, as part of a celebration of the journal’s 10th anniversary. Ke designed self-assembling DNA strands that would form a cylinder and a ring structure, let them assemble, and obtained images with transmission electron microscopy. The height of the final image is 120 nanometers, smaller than the wavelengths of visible light and about the size of an influenza or HIV virion.