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It is a privilege to work at Emory and learn about and report on so much quality biomedical research. I started to make a top 10 for 2014 and had too many favorites. After divertingÂ some of these topics into the 2015 crystal ball,Â I corralledÂ them into themes.
1. Cardiac cell therapy
PreSERVE AMI clinical trial led by cardiologist Arshed Quyyumi. Emory investigators developingÂ a variety ofÂ approaches to cardiac cell therapy.
2. Mobilizing the body’s own regenerative potential
Ahsan Husain’s work on how young hearts grow. Shan Ping Yu’s lab usingÂ parathyroid hormone boneÂ drug to mobilize cells for stroke treatment.
4. Parkinson’s disease therapeutic strategies
Container Store (Gary Miller, better packaging for dopamine could avoidÂ stress to neurons).
Anti-inflammatory (Malu Tansey, anti-TNF decoy can passÂ blood-brain barrier).
5. Personal genomics/exome sequencing
6. Neurosurgeons, likeÂ Emory’s Robert Gross and Costas Hadjpanayis, do amazing things
7. Fun vsÂ no fun
Fun = writing about Omar from The Wire in the context of drug discovery.
No fun (but deeply moving) = talking with patientsÂ fighting glioblastoma.
8. The hypersomnia field is waking up
Our Web expert tells me this was Lab Land’s most widely read post last year.
9. Fine-tuning approaches to cancer
10. Tie between fructose effects on adolescent brain (Constance Harrell/Gretchen Neigh) and flu immunology (embrace the unfamiliar! Ali Ellebedy/Rafi Ahmed)
Posted on January 7, 2015 by
A new paper in PNAS from geneticist Steve Warren and colleagues illustratesÂ the complexity of the protein disrupted in fragile X syndrome. It touches on how proposed drug therapies that address one aspect of fragile X syndrome may not be able to compensate for all of them. [For a human side of this story, read/listen to this recent NPR piece from Jon Hamilton.]
Fragile X syndrome is the most common single-gene disorder responsible for intellectual disability. Most patients with fragile X syndrome inherit it because a repetitive stretch of DNA, which is outside the protein-coding portion of the fragile X gene, is larger than usual. The expanded number of CGG repeats silences the entire gene.
However, simple point mutations affecting the fragile X protein are possible in humans as well. In the PNAS paper, Warrenâ€™s team describes what happens with a particularly revealing mutation, which allowed researchers to dissect fragile X proteinâ€™s multifaceted functions. Read more
Posted on January 5, 2015 by
Methylation, an epigenetic modification to DNA, can be thought of as a highlighting pen applied to DNAâ€™s text, adding information but not changing the actual letters of the text.
Are you still with me on the metaphors? If so, consider this wrinkle. (If not, more explanation here.)
Emory geneticist Peng Jin and his colleagues have been a key part of the discovery in the last few years that methylation comes in several colors. His lab has been mapping where 5-hydroxymethylcytosine or 5hmC appears in the genome and inferring how it functions. 5-hmC is particularly abundant in the brain.
Methylation, in the form of 5-methylcytosine or 5mC, is both a control button for turning genes off and a sign of their off state. 5hmC looks like 5mC, except it has an extra oxygen. That could be a tag for a removal, or a signal that aÂ gene is poised to be turned on.
Two recent papers on this topic:
Please recall that an enriched environment (exercise and mental stimulation) is good for learning and memory, for young and old. In the journalÂ Genomics, Jin and his team show that exposing mice to an enriched environmentÂ — a running wheel and a variety of toys — leads to a 60 percent reduction in 5hmC in the hippocampus, a region of the brain critical for learning and memory. Â The changes in 5hmC were concentratedÂ in genes having to do with axon guidance. Hat tip to the all-things-epigenetic site Epigenie.
In Genes and Development, structural biologist Xiaodong Cheng and colleagues demonstrateÂ that two regulatory proteins that bind DNA (Egr1 and WT1) respond primarily to oxidation of their target sequences rather than methylation. These proteins like plain old C and 5mC equally, but they donâ€™t like 5hmC or other oxidized forms of 5mC. â€œGene activity could plausibly be controlled on a much finer scale by these modifications than simply â€˜on or â€˜offâ€™,â€ the authors write.
Posted on October 8, 2014 by
Seth Mnookinâ€™s long piece in the New Yorker, on how social media accelerated the diagnosis of several children with a rare genetic disorder, is getting a lot of praiseÂ this week.Â This is the same story that was on CNN.com in March, titled â€œKids who donâ€™t cryâ€, and that Emory Genetics Laboratory director Madhuri Hedge mentioned as a recent diagnostic success for the technique of whole exome sequencing.
Briefly: parents of or doctors treating several children with a previously unknown metabolic disorder, with multiple symptoms — absent tear production, developmental delay, movement deficits, digestiveÂ problems etc — found each other via Internet searches/blog posts. The problems were traced back to mutations in the NGLY1 gene.
Emory geneticists Michael Gambello, Melanie Jones (now at the Greenwood Genetic Center in South Carolina) and Hegde are co-authors on the Genetics in Medicine paper that lays everything out scientifically.
Gambello, Jones and HegdeÂ were responsible for sequencing the DNA of a North Georgia family (they live inÂ Jackson County), whose members are mentioned in Mnookinâ€™s piece. The Gambello lab is developing an animal model of NGLY1 deficiency and is studying the mechanisms of how NGLY1 deficiency affects brain development.
Posted on July 18, 2014 by
Last year, pediatric gastroenterologist Subra Kugathasan gave an “old fashioned” grand rounds talk at Children’s Healthcare of Atlanta’s Egleston hospital, describing a family’s struggle with a multifaceted problem of autoimmunity.
Now the Journal of Pediatric Gastroenterology and Nutrition paper, on how the genetic alteration underlying the family’s struggles was identified, is published. Kugathasan reports that the young man at the center of the paper is scheduled for allogeneic bone marrow transplant in the United States (but not in Atlanta) in the next couple months.
The list of troubles the members of the family had to deal with is long: gastrointestinal issues and food allergies, skin irritation, bacterial + yeast infections, and arthritis. The mother and her brother were affected to some degree, as well as all three of the kids (see tree diagram). The youngest brother is the “proband”, a geneticist’s term for starting point.
As determined by whole exome sequencing, the gene responsible is FOXP3, which controls the development of regulatory T cells. These are cells that restrain the rest of the immune system; if they aren’t functioning correctly, the immune system is at war with the rest of the body, like in this family.
The genetic variant identified was new — that’s why whole exome sequencing was necessary to find it. The authors conclude:
Supporting the utility of WES [whole exome sequencing] in familial clusters of atypical IBD [inflammatory bowel disease], this approach led to a definitive diagnosis in this case, resulting in a justifiable treatment strategy of allogeneic bone marrow transplantation, the treatment of choice for IPEX [Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome].
Bone marrow transplant is a big deal; doctors are essentially wiping out the immune system then bringing it back, with several associated risks. So the decision to go ahead is not taken lightly. In general, whether bone marrow transplant — either autologous (patient donates back to self) or allogeneic (the donor is someone else) — is appropriate as a treatment for inflammatory bowel disease is still being investigated. Here, since a genetic origin is clear and there are autoimmune effects beyond the digestive system, it becomes the treatment of choice.
Posted on May 16, 2014 by
Peng Jin and collaborators led by Da-Hua Chen from the Institute of Zoology, Chinese Academy of Sciences have a new paper in Stem Cell Reports. They describe a souped-up method for producing iPS cells (induced pluripotent stem cells).
Production of iPS cells in the laboratory is becoming more widespread. Many investigators, including those at Emory, are using the technology to establish â€œdisease in a dishâ€ models and derive iPS cells from patient donations, turning them into tools for personalized medicine research.
Posted on February 27, 2014 by
The word “chaperone” refers to an adult who keeps teenagers from acting up at a dance or overnight trip. It also describes a type of protein that can guard the brain against its own troublemakers: misfolded proteins that are involved in several neurodegenerative diseases.
Researchers at Emory University School of Medicine led by Shihua Li, MD, and Xiao-Jiang Li, MD, PhDÂ have demonstrated that as animals age, their brains are more vulnerable to misfolded proteins, partly because of a decline in chaperone activity.
The researchers were studying a model of spinocerebellar ataxia, but the findings have implications for understanding other diseases, such as Alzheimer’s, Parkinson’s and Ray Ban outlet Huntington’s. They also identified targets for potential therapies: bolstering levels of either a particular chaperone or a growth factor in brain cells can protect against the toxic effects of misfolded proteins.
Posted on January 28, 2014 by
A team of researchers has discovered a genetic syndrome that causes childhood obesity, intellectual disability and seizures. The syndrome comes from an “unbalanced” chromosomal translocation: affected individuals have additional copies of genes from one chromosome and fewer copies of genes from another.
The results were published this week inÂ Proceedings of the National Academy of Sciences, Early Edition.
Katie Rudd, PhD, assistant professor of human http://www.raybanoutletes.com/ genetics at Emory University School of Medicine, is senior author of the paper. Research specialist Ian Goldlust, now a graduate student in the NIH-Oxford-Cambridge Scholars Program, is the first author. Co-authors include investigators from around the USA and Australia.
Rudd’s team was able to connect the contribution of one gene,Â GNB3, among many involved in the translocation, to the obesity aspect of the syndrome. Her lab created a mouse model with an extra copy of theÂ GNB3Â gene and found that the mice are obese. The mice are on average 6 percent (males) or 10 percent (females) heavier.
Rudd says her work was greatly assisted by collaboration with the Unique Rare Chromosome Disorder Support Group, a UK-based charity. Within Unique, a few parents had together found that their children had translocations involving the same chromosomes and similar symptoms. They contacted Rudd and helped her find additional affected families. Her study includes seven unrelated patients.
“It really was a group effort, and Unique was the linchpin,” she says. “Managing to find seven families with exactly the same rare translocation would have been extremely difficult otherwise.”
Posted on September 9, 2013 by
Move over, A, G, C and T. The alphabet of epigenetic DNA modifications keeps getting longer.
A year ago, we described research on previously unseen information in the genetic code using this metaphor:
Imagine reading an entire book, but then realizing that your glasses did not allow you to distinguish â€œgâ€ from â€œq.â€ What details did you miss?
Geneticists faced a similar problem with the recent discovery of a â€œsixth nucleotideâ€ in the DNA alphabet. Two modifications of cytosine, one of the four bases http://www.raybani.com/ that make up DNA, look almost the same but mean different things. But scientists lacked a way of reading DNA, letter by letter, and detecting precisely where these modifications are found in particular tissues or cell types.
Now, a teamâ€¦ has developed and tested a technique to accomplish this task.
Posted on April 19, 2013 by