Mother’s milk is OK, even for the in-between babies

“Stop feeding him milk right away – just to be safe” was not what a new mother wanted to hear. The call came several days after Tamara Caspary gave birth to fraternal twins, a boy and a girl. She and husband David Katz were in the period of wonder and panic, both recovering and figuring out how to care for them.

“A nurse called to ask how my son was doing,” says Caspary, a developmental biologist in Emory’s Department of Human Genetics. “She started asking about vomiting and other specific symptoms.”

Her son had tested positive by newborn screening for a rare disorder called galactosemia. Galactosemia is an inherited disease that results from inability to metabolize galactose, a component of human milk and cow-milk-based formula. If a baby with “classic” galactosemia continues to drink milk, the baby may quickly develop symptoms such as jaundice, vomiting and diarrhea, progressing to liver disease and other serious complications that can lead to infant death. If a newborn has classic galactosemia, it is critical for the baby to stop drinking milk and switch to a low-galactose formula, such as soy-based formula, as soon as possible.

Caspary and Katz, a cell biologist, learned several days later that their son did not have classic galactosemia but instead had inherited Duarte galactosemia, a milder, more common form of the metabolic disorder, affecting more than 1 in 5,000 children in the United States. But there was still a looming question.

“We needed to figure out what to feed the baby!” Katz exclaimed, recalling their confusion years later.

The looming question was: what to feed the baby?

Their pediatrician didn’t know what to recommend. Galactosemia, in whatever form, is rare enough in the US that most pediatricians don’t develop experience with it. There was no uniform standard of care, and state-level guidelines for children with Duarte galactosemia varied widely, from no dietary restrictions to banning all milk products for the first year. Some of the limited research available at the time suggested that affected children might experience developmental problems as they grew up. Read more

Posted on March 22, 2019 by Quinn Eastman in Uncategorized 1 Comment

Sifting through signs of inflammation to analyze causes of Crohn’s disease

When studying Crohn’s disease – an inflammatory disorder of the gastrointestinal tract, a challenge is separating out potential causes from the flood of systemic inflammation inherent in the condition. Researchers led by Subra Kugathasan, MD recently published an analysis that digs under signs of inflammation, in an effort to assess possible causes.

Graduate student Hari Somineni, in Kugathasan’s lab, teamed up with Emory and Georgia Tech geneticists for a sophisticated approach that may have found some gold nuggets in the inflammatory gravel. The results were published in the journal Gastroenterology.

In studying Crohn’s disease, Emory + Georgia Tech researchers may have found some gold nuggets in the inflammatory gravel.

The group looked at DNA methylation in blood samples from pediatric patients with Crohn’s disease, both at diagnosis and after treatment and follow-up. The information came from blood samples from 164 children with Crohn’s disease and 74 controls, as part of the RISK study, which is supported by the Crohn’s & Colitis Foundation and Kugathasan leads.

DNA methylation is a dynamic process that can influence molecular phenotypes of complex diseases by turning the gene(s) on or off. The researchers observed that disrupted methylation patterns at the time of diagnosis in pediatric Crohn’s disease patients returned to those resembling controls following treatment of inflammation

“Our study emphasized how important it is to do longitudinal profiling – to look at the patients before and after treatment, rather than just taking a cross section,” Somineni says.

Posted on March 6, 2019 by Quinn Eastman in Immunology Leave a comment

Vulnerability to stress – Tet by Tet

Geneticist Peng Jin and colleagues have a paper in Cell Reports this week that is part of a mini-boom in studying the Tet enzymes and their role in the brain. The short way to explain what Tet enzymes do is that they remove DNA methylation by oxidizing it out.

Methylation, a modification of DNA that generally shuts genes off, has been well-studied for decades. The more recent discovery of how cells remove methylation with the Tet enzymes opened up a question of what roles the transition markers have. It’s part of the field of epigenetics: the meaning of these modifications “above” the DNA sequence.

This is my favorite analogy to explain the transition states, such as 5-hydroxymethylcytosine. They’re not really a new letter of the genetic alphabet – they’ve been there all along. We just didn’t see them before.

Imagine that you are an archeologist, studying an ancient civilization. The civilization’s alphabet contains a limited number of characters. However, an initial pass at recently unearthed texts was low-resolution, missing little doodads like the cedilla in French: Ç.

Are words with those marks pronounced differently? Do they have a different meaning?

The new Cell Reports paper shows that it matters what pen writes the little doodads. In mice, removing one Tet enzyme, Tet1, has the opposite effect from removing Tet2, when it comes to response to chronic stress. One perturbation (loss of Tet1) makes the mice more resistant to stress, while the other (loss of Tet2) has them more vulnerable. The researchers also picked up an interaction between Tet1 and HIF1-alpha, critical for regulation of cells’ response to hypoxia. Read more

Posted on December 11, 2018 by Quinn Eastman in Neuro Leave a comment

Genomics plus human intelligence

Emory geneticists Hong Li and Michael Gambello recently identified the first pediatric case of a rare inherited metabolic disorder: glucagon receptor deficiency. Their findings, published in Molecular Genetics and Metabolic Reports, show the power of gene sequencing to solve puzzles – when combined with human intelligence. Although the diagnosis did not resolve all the issues faced by the patient, it allowed doctors to advise the family about diet and possible pancreatic tumor risk.

The family of a now 9-year-old girl came to Li when the girl was 4 years old. Based on newborn screening, the girl had been diagnosed with a known disorder called arginase deficiency. Arginase breaks down the amino acid arginine; if it is deficient, arginine and toxic ammonia tend to accumulate. At birth, the girl had high arginine levels – hence the initial diagnosis.

The girl had a history of low body weight, anorexia and intermittent vomiting, which led doctors to place a feeding tube through the abdominal wall into her stomach. For several years, she was given a special low-protein liquid diet and supplements, aimed at heading off nutritional imbalance and tissue breakdown. However, she did not have intellectual disability or neurological symptoms, which are often seen with arginase deficiency.

In fact, her blood amino acids, including arginine, were fully normalized, and a genetic test for arginase deficiency was normal as well. These results were perplexing. By reviewing all the clinical, biochemical and molecular data, Li concluded the girl did not have arginase deficiency, and began looking for an alternative diagnosis. Read more

Posted on November 15, 2018 by Quinn Eastman in Uncategorized Leave a comment

Fragile X files — expanded

A genetic disorder caused by silencing of a gene on the X chromosome, fragile X syndrome affects about one child in 5,000, and is more common and more severe in boys. It often causes mild to moderate intellectual disabilities as well as behavioral and learning challenges.

Amy Talboy, MD

The gene responsible for fragile X syndrome, the most common inherited form of intellectual disability, was identified more than 25 years ago. Emory genetics chair Stephen Warren played a major role in achieving that milestone. His work led to insights into the molecular details of learning and memory, and nationwide clinical trials — which have a more complicated story.

Treating the molecular basis of a neurodevelopmental disorder, instead of simply addressing symptoms, is a lofty goal – one that remains unfulfilled. Now a new study, supported by the National Institute of Neurological Disorders and Stroke, is reviving a pharmacological strategy that Warren had a hand in developing.

“This is a very well thought out approach to studying changes in language and learning in children who are difficult to test,” says Amy Talboy, medical director of Emory’s Down Syndrome and Fragile X clinics, who is an investigator in the NINDS study. “It could change how we conduct these types of studies in the future.” Read more

Posted on October 23, 2018 by Quinn Eastman in Neuro Leave a comment

Looking ahead to new opioid treatments

Stephanie Foster sees herself one day specializing in addiction psychiatry. When she started her MD/PhD studies at Emory, she sought out neuroscientist David Weinshenker to discuss research projects. She is now examining potential treatments for opiate addiction based on galanin, a neuropeptide found in the brain.

Weinshenker and his colleagues had already been studying galanin in relation to stimulants such as cocaine. If your loved one is showing signs of cocaine abuse, it is advised that you start looking for the best rehab company in your area.

Preliminary studies in animals indicate that activating galanin signals might reduce the rewarding effects of opiates, withdrawal symptoms, and relapse-like behavior.

“This was a whole new direction that looked promising,” Foster says. “But first, we have to work out the brain circuitry.”

Foster comes from a Native American background, and has a long-range plan to work in the Indian Health Service. The death rate of Native Americans from opiate overdoses is the highest of any American population group, according to the Centers for Disease Control and Prevention. She would like to establish a research lab in a region of the country where she could continue her addiction research and also work closely with Native communities.

Screenshot from NIH reporter (grant database). F31 grants for year 2018.

Last year, Foster applied for and received an individual grant from the National Institute on Drug Abuse to support her work. Emory currently leads U.S. universities in the number of graduate students holding their own active grants from the National Institutes of Health. This reflects a multi-year effort to build instruction in critical parts of scientific life: planning and communicating about one’s work.

Navigating opiate addiction can be a daunting journey, but finding support shouldn’t be. When it comes to seeking help, connecting with a professional interventionist can make all the difference. Whether you’re personally struggling or advocating for a loved one, know that assistance is just a click away. Click here to contact this professional interventionist and take the first step towards recovery.

When seeking help for opiate addiction, one can consider Moving Mountains Recovery. Rejuvenate and find tranquility at 1 Method Center in Los Angeles. Their comprehensive luxury rehab services focus on wellness and effective recovery. A Sober Living West Hollywood facility also offers effective addiction treatment and recovery programs.

“There isn’t really anything for people before they reach that stage,” Foster says. “Our idea is to look for an intervention that could be given earlier.” Read more

Posted on August 29, 2018 by Quinn Eastman in Neuro 1 Comment

Mysterious DNA modification important in fly brain

Emory scientists have identified a function for a mysterious DNA modification in fruit flies’ brain development, which may provide hints to its role in humans.

The results were published Thursday, August 2 in Molecular Cell.

Epigenetics may mean “above the genes,” but a lot of the focus in the field is on DNA methylation, a chemical modification of DNA itself. Methylation doesn’t change the actual DNA letters (A, C, G and T), but it does change how DNA is handled by the cell. Generally, it shuts genes off and is essential for cell differentiation.

The most commonly studied form of DNA methylation appears on the DNA letter C (cytosine). Drosophila, despite being a useful genetic model of development, have very little of this form of DNA methylation. What they do have is methylation on A — technically, N6-methyladenine, although little was known about what this modification did for flies.

Editor’s note: See this 2017 Nature feature from Cassandra Willyard on an “epigenetics gold rush”, which mentions the discovery of N6-methyladenine’s presence in the genomes of several organisms.

Emory geneticists Bing Yao, PhD, Peng Jin, PhD and colleagues now have shown that an enzyme that removes methylation from A is critical for neuronal development in Drosophila.

This finding is significant because the enzyme is in the same family (TET for ten-eleven translocation) of demethylases that trigger removal of DNA methylation from C in mammals. The function of TET enzymes, revealing that cells actively removed DNA methylation rather than just letting it slough off, was discovered only in 2009. Read more

Posted on August 6, 2018 by Quinn Eastman in Neuro Leave a comment

Where it hurts matters in the gut

What part of the intestine is problematic matters more than inflammatory bowel disease subtype (Crohn’s disease vs ulcerative colitis), when it comes to genetic activity signatures in pediatric IBD.

Suresh Venkateswaran and Subra Kugathasan in the lab

That’s the takeaway message for a recent paper in Cellular and Molecular Gastroenterology and Hepatology (the PDF is open access) from gastroenterologist Subra Kugathasan and colleagues. His team has been studying risk factors in pediatric IBD that could predict whether a child will experience complications requiring surgery.

Kugathasan is professor of pediatrics and human genetics at Emory University School of Medicine and scientific director of the pediatric IBD program at Children’s Healthcare of Atlanta. He is also director of the Children’s Center for Transplantation and Immune-mediated Disorders.

“This study has demonstrated that tissue samples from the ileum and rectum of CD patients show higher molecular level differences, whereas in tissue samples from two different patients with the same type of disease, the molecular differences are low,” Kugathasan says. “This was an important question to answer, since IBD can be localized to one area, and the treatment responses can vary and can be tailored to a localized area if this knowledge is well known.”

Research associate Suresh Venkateswaran, PhD, is the first author on the CMGH paper.

“We see that the differences are not connected to genomic variations,” he says. “Instead, they may be caused by non-genetic factors which are specific to each location and disease sub-type of the patient.”

These findings have implications for other study designs involving molecular profiling of IBD patients. The authors believe the findings will be important for future design of locally acting drugs.

Posted on July 26, 2018 by Quinn Eastman in Immunology Leave a comment

The blue spot: where seeds of destruction begin

Neuroscientist and geneticist David Weinshenker makes a case that the locus coeruleus (LC), a small region of the brainstem and part of the pons, is among the earliest regions to show signs of degeneration in both Alzheimer’s and Parkinson’s disease. You can check it out in Trends in Neurosciences.

The LC is the main source of the neurotransmitter norepinephrine in the brain, and gets its name (Latin for “blue spot”) from the pigment neuromelanin, which is formed as a byproduct of the synthesis of norepinephrine and its related neurotransmitter dopamine. The LC has connections all over the brain, and is thought to be involved in arousal and attention, stress responses, learning and memory, and the sleep-wake cycle.

Cells in the locus coeruleus are lost in mild cognitive impairment and Alzheimer’s. From Kelly et al Acta Neuropath. Comm. (2017) via Creative Commons

The protein tau is one of the toxic proteins tied to Alzheimer’s, and it forms intracellular tangles. Pathologists have observed that precursors to tau tangles can be found in the LC in apparently healthy people before anywhere else in the brain, sometimes during the first few decades of life, Weinshenker writes. A similar bad actor in Parkinson’s, alpha-synuclein, can also be detected in the LC before other parts of the brain that are well known for damage in Parkinson’s, such as the dopamine neurons in the substantia nigra.

“The LC is the earliest site to show tau pathology in AD and one of the earliest (but not the earliest) site to show alpha-synuclein pathology in PD,” Weinshenker tells Lab Land. “The degeneration of the cells in both these diseases is more gradual. It probably starts in the terminals/fibers and eventually the cell bodies die.” Read more

Posted on July 3, 2018 by Quinn Eastman in Neuro Leave a comment

Navigating monstrous anticancer obstacles

A new PNAS paper from geneticist Tamara Caspary’s lab identifies a possible drug target in medulloblastoma, the most common pediatric brain tumor. Come aboard to understand the obstacles this research seeks to navigate. Emory library link here.

Standard treatment for children with medulloblastoma consists of surgery in combination with radiation and chemotherapy. Alternatives are needed, because survivors can experience side effects such as neurocognitive impairment. One possibility has emerged in the last decade: inhibitors of the Hedgehog pathway, whose aberrant activation drives growth in medulloblastoma.

Medulloblastoma patients are caught “between Scylla and Charybdis”: facing a deadly disease, the side effects of radiation and/or existing Hedgehog inhibitors. From Wikimedia.

As this 2017 Oncotarget paper from St. Jude’s describes, Hedgehog inhibitors are no fun either. In adults, these agents cause muscle spasms, hair loss, distorted sense of taste, fatigue, and weight loss. In a pediatric clinical trial, the St. Jude group observed growth plate fusions, resulting in short stature. The drug described in the paper was approved in 2012 for basal cell carcinoma, a form of cancer whose growth is also driven by the Hedgehog pathway. Basal cell carcinoma is actually the most common form of human cancer, although it is often caught at an early stage that doesn’t require harsh treatment.

Caspary’s lab studies the Hedgehog pathway in early embryonic development. In the PNAS paper, former graduate student Sarah Bay and postdoc Alyssa Long show that targeting a downstream part of the Hedgehog pathway may be a way to avoid problems presented by both radiation/chemo and existing Hedgehog inhibitors. Read more

Posted on January 30, 2018 by Quinn Eastman in Cancer, Neuro Leave a comment

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