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Looking for Answers to Epilepsy in a Blood Test

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Gemma Carvill and lab members
Gemma Carvill (second from right) with members of her lab. Courtesy of Gemma Carvill

Millions of people take medications each day for epilepsy, a diverse group of disorders characterized by seizures. But, for about a third of people with epilepsy, current drug treatments don’t work very well. What’s more, the medications are designed to treat symptoms of these disorders, basically by suppressing seizure activity. The medications don’t really change the underlying causes, which are wired deep within the brain.

Gemma Carvill, a researcher at Northwestern University Feinberg School of Medicine, Chicago, wants to help change that in the years ahead. She’s dedicated her research career to discovering the genetic causes of epilepsy in hopes of one day designing treatments that can control or even cure some forms of the disorder [1].

It certainly won’t be easy. A recent paper put the number of known genes associated with epilepsy at close to 1,000 [2]. However, because some disease-causing genetic variants may arise during development, and therefore occur only within the brain, it’s possible that additional genetic causes of epilepsy are still waiting to be discovered within the billions of cells and their trillions of interconnections.

To find these new leads, Carvill won’t have to rely only on biopsies of brain tissue. She’s received a 2018 NIH Director’s New Innovator Award in search of answers hidden within “liquid biopsies”—tiny fragments of DNA that research in other forms of brain injury and neurological disease [3] suggests may spill into the bloodstream and cerebrospinal fluid (CSF) from dying neurons or other brain cells following a seizure.

Carvill and team will start with mouse models of epilepsy to test whether it’s possible to detect DNA fragments from the brain in bodily fluids after a seizure. They’ll also attempt to show DNA fragments carry telltale signatures indicating from which cells and tissues in the brain those molecules originate. The hope is these initial studies will also tell them the best time after a seizure to collect blood samples.

In people, Carvill’s team will collect the DNA fragments and begin searching for genetic alterations to explain the seizures, capitalizing on Carvill’s considerable expertise in the use of next generation DNA sequencing technology for ferreting out disease-causing variants. Importantly, if this innovative work in epilepsy pans out, it also can be applied to any other neurological condition in which DNA spills from dying brain cells, including Alzheimer’s disease and Parkinson’s disease.

References:

[1] Unravelling the genetic architecture of autosomal recessive epilepsy in the genomic era. Calhoun JD, Carvill GL. J Neurogenet. 2018 Sep 24:1-18.

[2] Epilepsy-associated genes. Wang J, Lin ZJ, Liu L, Xu HQ, Shi YW, Yi YH, He N, Liao WP. Seizure. 2017 Jan;44:11-20.

[3] Identification of tissue-specific cell death using methylation patterns of circulating DNA. Lehmann-Werman R, Neiman D, Zemmour H, Moss J, Magenheim J, Vaknin-Dembinsky A, Rubertsson S, Nellgård B, Blennow K, Zetterberg H, Spalding K, Haller MJ, Wasserfall CH, Schatz DA, Greenbaum CJ, Dorrell C, Grompe M, Zick A, Hubert A, Maoz M, Fendrich V, Bartsch DK, Golan T, Ben Sasson SA, Zamir G, Razin A, Cedar H, Shapiro AM, Glaser B, Shemer R, Dor Y. Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):E1826-34.

Links:

Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Gemma Carvill Lab (Northwestern University Feinberg School of Medicine, Chicago)

Carvill Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke


Moving Toward Answers in ME/CFS

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Woman in bed

Thinkstock/Katarzyna Bialasiewicz

Updated September 27, 2017: The National Institutes of Health (NIH) will award four grants to establish a coordinated scientific research effort on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The total cost of the projects for fiscal year 2017 will be over $7 million, with support from multiple NIH Institutes and Centers that are part of the Trans-NIH ME/CFS Working Group.

The grants will support the creation of a consortium made up of three Collaborative Research Centers (CRC) and a Data Management Coordinating Center (DMCC). The CRCs will each conduct independent research but will also collaborate on several projects, forming a network to help advance knowledge on ME/CFS. The data will be managed by the DMCC and will be shared among researchers within the CRCs and more broadly with the research community.


Imagine going to work or school every day, working out at the gym, spending time with family and friends—basically, living your life in a full and vigorous way. Then one day, you wake up, feeling sick. A bad cold maybe, or perhaps the flu. A few days pass, and you think it should be over—but it’s not, you still feel achy and exhausted. Now imagine that you never get better— plagued by unrelenting fatigue not relieved by sleep. Any exertion just makes you worse. You are forced to leave your job or school and are unable to participate in any of your favorite activities; some days you can’t even get out of bed. The worst part is that your doctors don’t know what is wrong and nothing seems to help.

Unfortunately, this is not fiction, but reality for at least a million Americans—who suffer from a condition that carries the unwieldy name of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a perplexing disease that biomedical research desperately needs to unravel [1]. Very little is currently known about what causes ME/CFS or its biological basis [2]. Among the many possibilities that need to be explored are problems in cellular metabolism and changes in the immune system.


What Is Obesity? Metabolic Signatures Offer New Comprehensive View

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Silhouettes over an NMR

Credit: Adapted from Elliott, P et al., Sci Transl Med. 2015 Apr 29;7(285)

As obesity has risen in the United States and all around the world, so too have many other obesity-related health conditions: diabetes, heart disease, stroke, cancer, and maybe even Alzheimer’s disease. But how exactly do those extra pounds lead to such widespread trouble, and how might we go about developing better ways to prevent or alleviate this very serious health threat?

In a new study in Science Translational Medicine [1], researchers performed sophisticated analyses of the molecules excreted in human urine to produce one of the most comprehensive pictures yet of the metabolic signature that appears to correlate with obesity. This work provides a fascinating preview of things to come as researchers from metabolomics, microbiomics, and a wide variety of other fields strive to develop more precise approaches to managing and preventing disease.


Metabolomics: Taking Aim at Diabetic Kidney Failure

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Patients with red tubes attached to their arms

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Caption: Dialysis is often used to treat kidney failure related to diabetes.

My own research laboratory has worked on the genetics of diabetes for two decades. One of my colleagues from those early days, Andrzej Krolewski, a physician-scientist at the Joslin Diabetes Center in Boston, wondered why about one-third of people with type 2 diabetes eventually develop kidney damage that progresses to end-stage renal disease (ESRD), but others don’t. A stealthy condition that can take years for symptoms to appear, ESRD occurs when the kidneys fail, allowing toxic wastes to build up. The only treatments available are dialysis or kidney transplants.