DNA usually occupies a privileged place inside the cell. Although cells in our body die all the time, an orderly process of disassembly (programmed cell death or apoptosis) generally keeps cellular DNA from leaking all over the place. DNA’s presence outside the cell means something is wrong: tissue injury has occurred and cells are undergoing necrosis.
Researchers from the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University have devised a way to exploit the properties of extracellular DNA to create an imaging agent for injured tissue. Niren Murthy and Mike Davis recently published a paper in Organic Letters describing the creation of â€œHoechst-IR.â€ This imaging agent essentially consists of the DNA-binding compound Hoechst 33258 (often used to stain cells before microscopy), attached to a dye that is visible in the near-infrared range. A water-loving polymer chain between the two keeps the new molecule from crossing cell membranes and binding DNA inside the cell.
Itâ€™s not a silly question, when one sees how oxidative stress and reactive oxygen species have been implicated in so many diseases, ranging from hypertension and atherosclerosis to neurodegenerative disorders. Yet large-scale clinical trials supplementing participantsâ€™ diets with antioxidants have showed little benefit.
Emory University School of Medicine scientists have arrived at an essential insight: the cell isnâ€™t a tiny bucket with all the constituent chemicals sloshing around. To modulate reactive oxygen species effectively, an antioxidant needs to be targeted to the right place in the cell.
Sergei Dikalov and colleagues in the Division of Cardiology have a paper in the July 9 issue ofÂ Circulation Research, describing how targeting antioxidant molecules to mitochondria dramatically increases their effectiveness in tamping down hypertension.
Mitochondria are usually described as miniature power plants, but in the cells that line blood vessels, they have the potential to act as amplifiers. The authors describe a â€œvicious cycleâ€ of feedback between the cellular enzyme NADPH oxidase, which produces the reactive form of oxygen called superoxide, and the mitochondria, which can also make superoxide as a byproduct of their energy-producing function.
Emory geneticist Peng Jin and his colleagues have a review in the June 25, 2010 issue ofÂ Chemistry and Biology exploring whether microRNAs offer new possibilities for pharmacology.
MicroRNAs directly regulate other genes
The microRNA pathway represents both a way for scientists to “knock down” the activity of just one gene in the laboratory, and a major way for cells to regulate their genes during development.
MicroRNAs add a big wallop of complexity on top of the standard model of molecular biology, where the information in DNA is made into RNA, and RNAs make proteins. MicroRNAs don’t get turned into protein, but directly regulate other genes.
Andrew Fire and Craig Mello received the 2006 Nobel Prize in Medicine for their discovery that short pieces of RNA, when introduced into cells, can silence genes. This “RNA interference” tactic hijacks the natural machinery inside the cell that microRNAs use.
In 2008, Jin and coworkers published in Nature Biotechnology their discovery that certain antibiotics called fluoroquinolones (ciprofloxacin is one) can make the RNA interference process work more efficiently — in general. In the review, Jin notes that scientists are starting to look for drugs that act more selectively, disrupting or enhancing a particular microRNA rather than many at once:
Since miRNAs play major roles in nearly every cellular process, the identification and characterization of small-molecule modulators of the RNAi/miRNA pathway will yield fresh insights into fundamental mechanisms behind human disease… Moreover, these RNAi modulators, particularly RNAi enhancers, could potentially facilitate the development of RNA interference as a tool for biomedical research and therapeutic interventions.
Last year, when the H1N1 flu epidemic was a major public health concern, a relatively low proportion of individuals getting sick were elderly, compared to previous flu epidemics. To explain this, scientists hypothesized that flu strains that circulated decades ago were similar enough to the novel swine-origin H1N1 strain toÂ provide some immune protection.
A universal flu vaccine would eliminate the guesswork associated with the yearly flu shot
Now, researchers at Emory’s Influenza Pathogenesis & Immunology Research Center have directly tested that hypothesis in mice, and it holds up. Exposure of mice to flu strains that circulated in 1947 or 1934 induced “robust cross-protective immune responses” and can protect them against a lethal challenge with 2009 H1N1 virus, they report in Journal of Immunology.
Ioanna Skountzou and Dimitrios Koutsananos are co-first authors of the paper.
The Emory team, led by Joshy Jacob, also reports that antibodies produced in response to the 2009 H1N1 flu strain exhibit broad cross-reactivity — they react with other H1N1 strains as well as against H3N2 flu strains. They write:
The fact that the 2009 H1N1 virus can induce such cross-reactive Abs raises the intriguing possibility that viruses such as A/California/04/2009 can be used for vaccines to induce broadly cross-reactive humoral immune responses against influenza viruses. Identifying the mechanism behind this broad reactivity may enable us to design broadly cross-reactive universal influenza vaccines.
National Institute of Allergy and Infectious Diseases director Tony Fauci, when he was at Emory for the H1N1 flu conference in April, discussed the idea of a universal flu vaccine:
Kathy Griendling, PhD (in green), surrounded by members of her lab
On June 15, 2010, vascular biologist Kathy Griendling delivered the 2010 Dean’s Distinguished Faculty lecture at Emory University School of Medicine.
Some of Griendling’s publications have been cited thousands of times by fellow scientists around the world, making her the lead member of a small group of researchers at Emory called theÂ “Millipub Club.”
With her five children and one grandson watching in the back row, Griendling explained how she and her colleagues, over the course of more than two decades at Emory, have gradually revealed the functions of a family of enzymes called NADPH oxidases in vascular smooth muscle cells. Read more
A recent article in Nature describes the resurgence of interest in cancer cell metabolism. This means exploiting the unique metabolic dependencies of cancer cells, such as their increased demand for glucose.
Cancer cells' preference for glucose is named after 1931 Nobelist Otto Warburg
Otto Warburg, who won the Nobel Prize in Medicine in 1931, noticed that cancer cells have a “sweet tooth” decades ago, but only recently have researchers learned enough about cancer cells’ regulatory circuitry to possibly use this to their advantage.
AtÂ Winship Cancer Institute of Emory University, several scientists have been investigating aspects of this phenomenon. Jing Chen and his team have identified a switch, the enzyme pyruvate kinase, which many types of cancer use to control glucose metabolism, and that might be a good drug target.
Jing Chen, PhD, and Taro Hitosugi, PhD
Shi-Yong Sun, Wei Zhou and their colleagues have found that cancer cells are sneaky: blockade the front door (for glucose metabolism, this means hitting them with the chemical 2-deoxyglucose) and they escape out the back by turning on certain survival pathways. This means combination tactics or indirectly targeting glucose metabolism through the molecule mTOR might be more effective, the Nature article says.
A quote from the article:
Clearly, metabolic pathways are highly interconnected with pathways that govern the hallmarks of cancer, such as unrestrained proliferation and resistance to cell death. The many metabolic enzymes, intermediates and products involved could be fertile ground for improving cancer diagnostics and therapeutics.
B cells are workhorses of the immune system. Their main function is to produce antibodies against bacteria or viruses when they encounter something that they recognize.Â But recently researchers have been getting hints that certain kinds of B cells can also have a calming effect on the immune system. This property could come in handy with hard-to-treat conditions such as graft-vs-host disease, multiple sclerosis, or Crohn’s disease.
Hematologist Jacques Galipeau has found that B cells treated with an artificial hybrid molecule called GIFT15 turn into “peacemakers”. These specially treated B cells can tamp down the immune system in an experimental animal model of multiple sclerosis, suggesting that they could accomplish a similar task with the human disease.
Galipeau’s paper inÂ Nature Medicine from August 2009 says succinctly: “We propose that autologous GIFT15 B regulatory cells may serve as a new treatment for autoimmune ailments.”Â Galipeau, a recent arrival to Emory from McGill University in Montreal, explains this tactic and other aspects of personalized cell therapy in the video above. Read more
Former National Institutes of Health director Elias Zerhouni created a vivid label for a persistent problem. He noted there was a widening gap between basic and clinical research. The “valley of death” describes the gap between basic research, where the majority of NIH funding is directed and many insights into fundamental biology are gained, and patients who need these discoveries translated to the bedside and into the community in order to benefit human health. Thus, a chasm has opened up between biomedical researchers and the patients who would benefit from their discoveries.
Translational research seeks to move ideas from the laboratory into clinical practice
Translational research seeks to move ideas from the laboratory into clinical practice in order to improve human health.
A new certificate program in translational research is designed to empower PhD graduate students to bridge that gap. Participants (PhD graduate students) from Emory, Georgia Tech and Morehouse School of Medicine can take courses in epidemiology, biostatistics, bioethics, designing clinical trials and grant writing, and will have rotations with clinicians and clinical interaction network sites where clinical research studies are carried out to get a better sense of the impact and potential benefit of the research they are conducting.
View of MR/PET scanner from front, with Ciprian Catana of MGH and Larry Byars of Siemens
The scanner is one of four world-wide and one of two in the United States, and permits simultaneous MR (magnetic resonance) and PET (positron emission tomography) imaging in human subjects. This provides the advantage of being able to combine the anatomical information from MR with the biochemical/metabolic information from PET. Potential applications include functional brain mapping and the study of neurodegenerative diseases, drug addiction and brain cancer.
Thursday’s event brought together leaders of the three other MR/PET programs in Boston, JÃ¼lich and TÃ¼bingen, the Siemens engineers who designed the device, and the Atlanta research community to explore the possibilities of the technology.
The drugs now available to treat Alzheimer’s address the symptoms of the disease — memory problems — rather than the underlying mechanism of neurodegeneration.
But what if something could do both? Here’s a tantalizing prospect, hinted at by a long-running thread of brain research: compounds that boost the function of certain acetylcholine circuits in the brain might also modify production of toxic beta-amyloid protein.
The possibility grows out of the properties of certain receptors for the neurotransmitter acetylcholine, called “muscarinic acetylcholine receptors.” Acetylcholine is a major transmitter of signals in the brain, and there are several varieties of receptors, or receiver dishes for the signals, on brain cells.