NADPH oxidases (Nox for short) are enzymes that help plants fight off pathogens, guide sexual development in fungi, are essential for egg laying in flies and even help humans to sense gravity.
But what first attracted the interest of Emory researchers was the role of Nox in vascular disease and cancer. Along with Emory cardiologist Kathy Griendling, pathologist David Lambethpioneered the discovery of how important these reactive oxygen-generating enzymes really are.
One of the Emory SFN presentations covered efforts to find progesterone analogues that are more water soluble. This work comes from Stein and his colleagues in collaboration with the laboratory of Dennis Liotta, PhD, Emory professor of chemistry.
Currently, the lack of water solubility limits delivery of progesterone, in that the hormone must be prepared hours ahead and cannot be kept at room temperature. Small chemical modifications may allow similar compounds with the same effects as progesterone to be given to patients closer to the time of injury.
According to the results, two compounds similar to progesterone showed an equivalent ability to reduce brain swelling in an animal model of traumatic brain injury.
The second Emory report described evidence that adding vitamin D to progesterone enhances the hormone’s effectiveness when applied to neurons under stress in the laboratory. Like progesterone, vitamin D is a steroid hormone that is inexpensive, has good safety properties and acts on many different biochemical pathways.
David Wright, MD
The authors showed that a low amount of vitamin D boosted the ability of progesterone to protect neurons from excito-toxicity , a principal cause of brain injury and cell death.
A new study at Emory, slated to begin early 2010, will evaluate progesterone’s effectiveness for treating traumatic brain injury in a multisite phase III clinical trial called ProTECT III.
The study follows earlier findings that showed giving progesterone to trauma victims shortly after brain injury appears to be safe and may reduce the risk of death and long-term disability.
David Wright, MD, assistant professor of emergency medicine at Emory School of Medicine is the national studyâ€™s lead investigator.
Michael Frankel, MD, Emory professor of neurology, will serve as site principal investigator of the clinical trial at Grady Memorial Hospital.
Jorg Goronzy, MD, PhD and Cornelia Weyand, MD, PhD
Weyand and Goronzy show that with age, T cells begin to turn on genes that are usually turned on only in â€œnatural killerâ€ cells. NK cells play a major role in rejecting tumors and killing cells infected by viruses. They are white blood cells like T cells but they have a different set of receptors on their surfaces controlling their activities.
Many of these receptors act to hold the NK cells back; so when they appear on the T cells, their activation is dampened too, thus contributing to the slowing down of the immune system in elderly people.
The authors report that NK cell genes get turned on because they lose the â€œmethylationâ€ on their DNA. Methylation is a pattern of tiny modifications on DNA, emphasizing whatâ€™s important (or forbidden) in a given cell, sort of like a highlighterâ€™s yellow pen on top of text.
Apparently, in elderly people (aged 70-85), the methylation is more â€œspottyâ€ than in younger people (aged 20-30). It seems that after the DNA is copied several times, the highlighting gets fuzzy and the T cells start to look like their cousins, natural killer cells.
Much of the time in biochemistry, when you want to know what’s happening inside a cell you have to break them open.
Fluorescent proteins are a great tool and deserved their Nobel Prize. But you have to convince your favorite cells to make the fluorescent proteins first. It’s possible to think of specialized non-invasive probes too: dyes that change color when they encounter calcium, for example.
Now imagine being able to decipher what’s going on inside cells simply by looking at them and watching the proteins and organelles shift in response to signals. That’s essentially what Yuhong Du and Haian Fu at the Emory Chemical Biology Discovery Center have been able to do.
They use an “optical biosensor” which puts cells in front of a reflective grating. Depending on how the grating reflects light, they can measure mass redistribution inside the cells.
How the optical biosensor works
With this technology, they could watch for responses as cancer cells responded to signals from EGFR (epidermal growth factor receptor).
Drugs such as gefitinib and erlotinib are supposed to block those growth signals in lung cancer cells, but not every cancer responds to them. These results suggest that the optical biosensor system could be used to screen for compounds that block EGFR and many other receptors, potentially speeding up the hunt for drugs against several diseases.
Congratulations to Elizabeth Blackburn, Carol Greider and Jack Szostak for the 2009 Nobel Prize in medicine. The award is for their work on telomeres, the protective caps on the ends of chromosomes that shorten with every cell division and need specialized enzymes to be replenished.
Greider, Blackburn and Szostak discovered telomerase, the enzyme that copies the ends of chromosomes using a special RNA template. Telomerase is turned off in most human cells, but cancer cells often must reactivate it so that they can keep dividing like crazy.
The discovery of telomerase has led to new leads for potential anticancer drugs. This is a good example of the impact basic research can have on medicine, since the prize-winners were not thinking about anticancer drugs in the 1980s when they were doing their work.
Telomeres are specialized protective structures at the ends of chromosomes
The telomere trioâ€™s work relates to several lines of research at Emory.
Immunologist Cornelia Weyand and her colleagues have shown that the telomeres of T cells are abnormally shortened in patients with rheumatoid arthritis. In effect, their cells’ chromosomes are prematurely aged. This result provides some hints on how to treat autoimmune diseases.
If blood-forming stem cells can’t keep their telomeres in shape, they can’t continue to regenerate the blood. Pathologist Hinh Ly’s research has made a connection betweenÂ genetic defects in telomere maintenance and bone marrow failure syndrome in human patients.
Geneticists Christa Martin and David Ledbetter have been probing the relationship between mutations or recombination in the regions of the chromosome adjacent to telomeres and developmental disorders such as autism and mental retardation.
â€œThe past is difficult to recover because it was built on the foundation of its own history, one irrevocably different from that of the present and its many possible futures.â€
Whoa. This quote comes from a recent Nature paper. How did studying the protein that helps cells respond to the stress hormone cortisol inspire such philosophical language?
Biochemist Eric Ortlund at Emory and collaborator Joe Thornton at the University of Oregon specialize in â€œresurrectingâ€and characterizing ancient proteins. They do this by deducing how similar proteins from different organisms evolved from a common root, mutation by mutation. Sort of like a word ladder puzzle.
Ortlund and Thornton have been studying the glucocorticoid receptor, a protein that binds the hormone cortisol and turns on genes in response to stress. The glucocorticoid receptor is related to the mineralocorticoid receptor, which binds hormones such as aldosterone, a regulator of blood pressure and kidney function.
If these receptors have a common ancestor, you can model each step in the transformation that led from the ancestor to each descendant. But Ortlund says that protein evolution isnâ€™t like a word ladder puzzle, which can be turned upside-down: â€œYou canâ€™t rewind the tape of life and have it take the same path.â€
The reason: Mutations arise amidst a background of selective pressure, and mutations in one part of a protein set the stage for whether other ones will be viable. The researchers describe this as an â€œepistatic rachetâ€.
Mutations that occurred during the transformation between the ancestral protein (green) and its descendant (orange) would clash if put back to their original position.
This work highlights the increasing number of structural biologists like Ortlund, Christine Dunham, Graeme Conn and Xiaodong Cheng at Emory. Structural biologists use techniques such as X-ray crystallography to figure out how the parts of biologyâ€™s machines fit together. Recently Emory has been investing in the specialized equipment necessary to conduct X-ray crystallography.
As part of his future plans, Ortlund says he wants to go even further back in evolution, to examine the paths surrounding the estrogen receptor, which is also related to the glucocorticoid receptor.
Besides giving insight into the mechanisms of evolution, Ortlund says his research could also help identify drugs that activate members of this family of receptors more selectively. This could address side effects of drugs now used to treat cancer such as tamoxifen, for example, as well as others that treat high blood pressure and inflammation.
Emory Vaccine Center researcher Cynthia Derdeyn and her colleagues have a new paper in PLOS Pathogens that is a reality check for researchers designing possible HIV vaccines. The results come from a collaboration with the Rwanda Zambia HIV Research Group. (Although the patients in this paper are from Zambia only.)
Red and green depict the parts of the HIV envelope protein that mutated in two patients (185F and 205F) in response to pressure from their immune systems.
Recently there has been some excitement over the discovery of robust neutralizing antibodies in patients.
The bottom line, according to Derdeyn’s team: even if a vaccine succeeds in stimulating antibodies that can neutralize HIV, the virus is still going to mutate furiously and may escape those antibodies. To resist HIV, someone’s immune system may need to have several types of antibodies ready to go, their results suggest.
A companion paper in the same issue of PLOS Pathogens from South African scientists has similarly bracing results.
The case report describes a woman with diabetes who needed surgery because of loss of blood flow to abdominal organs. While she is in intensive care after surgery, it becomes clear that a feeding tube leading from her nose to her stomach is not working. That makes her a good candidate for parenteral nutrition, or bypassing the digestive system and delivering nutrients directly into her blood.
Malnutrition is common in patients who are critically ill and often worsens with prolonged hospitalization. Some patients can’t eat normal food or benefit from a feeding tube into the stomach.
Thomas Ziegler, MD, Director, Center for Clinical and Molecular Nutrition, Department of Medicine
Yet few well-designed clinical trials studying parenteral nutrition have been conducted, Ziegler writes. He also notes that there is considerable debate over when parenteral nutrition is appropriate during critical care and how to administer it.
Ziegler’s own research has shown the beneficial effects of the amino acid glutamine, which must be added fresh to feeding formulas, for some critical care patients.
Several of the questions Ziegler outlines in his article will be issues investigators at Emory’s new Center for Critical Care will tackle. Recently, Timothy Buchman, MD, PhD, joined Emory to lead the critical care team.
The idea that doctors could use stem cells to treat diseases ranging from amyotrophic lateral sclerosis (ALS) to stroke, spinal cord injury and heart disease has stimulated excitement and research funding over the last decade.
One critical obstacle is getting the stem cells to survive in the harsh environment of injured tissue and turn into the right kind of cell where they are needed. In both laboratory experiments and clinical trials, most of the stem cells usually die a few days after transplantation.
Exposing stem cells to reduced levels of oxygen may actually help protect them from the stressful process of being transplanted into the heart, according to recent research.
Shan Ping Yu and Ling Wei, who moved their laboratories about a year ago to Emoryâ€™s Department of Anesthesiology, were the first to show the effects of “hypoxic preconditioning.” Wei says the low oxygen strategy is a continuation of previous collaboration with Comprehensive Neurosciences Center director Dennis Choi. There, they had used the tactic of overexpressing BCl2, a gene that counteracts cell death, but the new approach avoids permanently altering the genes in stem cells, which may have long-term adverse effects.
Effects on mesenchymal stem cells' ability to implant into heart tissue in rats. In D, the stem cells were exposed to low oxygen but in C they were not. Blue shows all cell nuclei, while green shows implanted stem cells. The greater presence of yellow in C, a couple days after transplantation, displays the activation of an enzyme that leads to cell death. From the Journal of Thoracic and Cardiovascular Surgery.
In a way, this is consistent with the work of former Emory investigator Marie Csete, who showed that stem cells are happier and healthier in oxygen concentrations that reflect the levels they experience in the body: between 2 and 5%.
To achieve their protective effects, Yu and Wei are using oxygen concentrations of 0.5%. For comparison, room air has about 20% oxygen.
In an editorial, Yu, Wei and graduate student Molly Ogle discuss how they have been exploring whether inhibitors of enzymes that sense levels of oxygen in cells could have the same protective effects as exposure to low oxygen. Yu also reports that his group is studying how low oxygen helps stem cells home to target tissues better. Their hypothesis is that low oxygen stimulates cellsâ€™ motility — their ability to migrate into the right place. Wei’s research has shown that lower oxygen helps more stem cells to turn into neuronal cells.
An Emory project studying schizophrenia genetics is a good example of how geneticists are shifting from examining small, common mutations to “rare variants” when studying complex diseases.
From studies of twins, doctors have known for a long time that heredity plays a big role in causing schizophrenia. But dissecting out which genes are the most important has been a challenge.
Threelandmarkstudies on schizophrenia genetics published this summer illustrate the limitations of “genome wide association” studies. New York Times science reporter Nicholas Wade summarized the results in this way:
“The principal news from the three studies is that schizophrenia is caused by a very large number of errant genes, not a manageable and meaningful handful.”
The limitations from this type of study comes from the type of markers geneticists are looking at, says Steve Warren, chair of the human genetics department at Emory.
Genome wide association studies usually follow SNPs — single nucleotide polymorphisms. This is a one-letter change somewhere in the genetic code that is found in a fraction of the population. It’s not a big change in the genome, and in many cases, it will have a small effect on disease risk.
Researchers looking for the genes behind complex diseases such as schizophrenia and autism are starting to shift their efforts away from genome wide association studies, Warren says.
Think of a SNP like a misspelling of a word in a certain place in a book, he says. In contrast, the “rare variants” geneticists are starting to study more intensively are more like printers’ errors or missing pages. The rapid sequencing technology that allows scientists to investigate these changes easily is just now coming on line, he says.
One example of these rare variants is DiGeorge syndrome, a deletion that gets rid of dozens of genes on one copy of chromosome 22. Children who have this chromosomal alteration often have anatomical changes to their heart and palate. But it also substantially increases the risk of schizophrenia – to about 25% lifetime risk. That’s a lot more than any of the SNPs identified this summer.
Working with several Emory colleagues, researcher Brad Pearce is planning to examine the genes missing in DiGeorge syndrome in several groups of patients: people with DiGeorge, patients with “typical” schizophrenia and people at high risk of developing schizophrenia.
An article in this spring’s Emory Health describes genetic research on autism. Several of the researchers mentioned there, such as geneticist Joe Cubells and psychiatrist Opal Ousley, are involved in this schizophrenia project as well, because deletions on chromosome 22 also lead to an increased risk of autism.