Vulnerability to stress - Tet by Tet

Transition states like 5-hydroxymethylcytosine aren't really a new letter of the genetic alphabet – they’ve been there all along. We just didn’t see them Read more

Circadian rhythms go both ways: in and from retina

Removal of Bmal1 accelerates the deterioration of vision that comes with Read more

Genomics plus human intelligence

The power of gene sequencing to solve puzzles when combined with human Read more

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Retaining the resistance: MCR-1, colistin + lysozyme

If you’ve been following the news about antibiotic resistant bacteria, you may have heard about a particularly alarming plasmid: MCR-1. A plasmid is a circle of DNA that is relatively small and mobile – an easy way for genetic information to spread between bacteria. MCR-1 raises concern because it provides bacteria resistance against the last-resort antibiotic colistin. The CDC reports MCR-1 was found in both patients and livestock in the United States this summer.
David Weiss, director of Emory’s Antibiotic Resistance Center, and colleagues have a short letter in The Lancet Infectious Diseases showing that MCR-1 also confers resistance to an antimicrobial enzyme produced by our bodies called lysozyme. MCR-1-containing strains were 5 to 20 times less susceptible to lysozyme, they report.
This suggests that the pressure of fighting the host immune system may select for MCR-1 to stick around, even in the absence of colistin use, the authors say.
While the findings are straightforward in bacterial culture, Weiss cautions that there is not yet evidence showing that this mechanism occurs in live hosts. For those that really want to get alarmed, he also calls attention to a recent Nature Microbiology paper describing a hybrid plasmid with both MCR-1 and resistance to carbapenem, another antibiotic.

Read more

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Gestational age estimated via DNA methylation

Researchers have developed a method for estimating developmental maturity of newborns. It is based on tracking DNA methylation, a structural modification of DNA, whose patterns change as development progresses before birth.

The new method could help doctors assess developmental maturity in preterm newborns and make decisions about their care, or estimate the time since conception for a woman who does not receive prenatal care during pregnancy. As a research tool, the method could help scientists study connections between the prenatal environment and health in early childhood and adulthood.

How advanced is the development of a newborn, possibly preterm baby? Geneticists have developed a method for estimating gestational age by looking at DNA methylation.

The study, led by Alicia Smith, PhD and Karen Conneely, PhD, used blood samples from more than 1,200 newborns in 15 cohorts from around the world. The results are published in Genome Biology.

Smith is an associate professor and vice chair of research for the Department of Gynecology and Obstetrics in the School of Medicine, and Conneely is an assistant professor in the Department of Human Genetics. The first author, Anna Knight, is a graduate student in the Genetics and Molecular Biology Program.

Gestational age, is normally estimated by obstetricians using ultrasound during the first trimester, by asking a pregnant woman about her last menstrual period, or by examining the baby at birth. Ultrasound is considered to be the most precise estimate of gestational age. This work extends upon earlier studies of DNA methylation patterns that change over development and predict age and age-related health conditions in children and adults.

The Emory team gathered DNA methylation data from previous studies examining live births and health outcomes, and used an unbiased statistical learning approach to select 148 DNA methylation sites out of many thousands in the genome. By examining methylation at those sites, gestational age could be accurately estimated between 24 and 44 weeks, the authors report. The median difference between age determined by DNA methylation and age determined by an obstetrician estimate was approximately 1 week.

The researchers also found that the difference between a newborn’s age predicted by DNA methylation and by an obstetrician may be another indicator of developmental maturity, and is correlated with birthweight, commonly used as an indicator of perinatal health. Read more

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Strength tests for platelets

Bleeding disorders could one day be diagnosed by putting platelets through strength tests, researchers have proposed.

Biomedical engineers from Emory and Georgia Tech have devised a microfluidic testing ground where platelets can demonstrate their strength by squeezing two protein dots together. Imagine rows and rows of strength testing machines from a carnival, but very tiny. Platelets are capable of exerting forces that are several times larger, in relation to their size, in comparison with muscle cells.

After a blood clot forms, it contracts, promoting wound closure and restoration of normal blood flow. This process can be deficient in a variety of blood clotting disorders. Previously, it was difficult to measure individual platelet’s contributions to contraction, because clots’ various components got in the way.

The prototype diagnostic tools are described in Nature Materials.

platelet_strength_test

Top: platelets exert their strength. Bottom left: red = platelets, green = fibrinogen dots. Bottom right: size of actual device.

“We discovered that platelets from some patients with bleeding disorders are ‘wimpier’ than platelets from healthy people,” says Wilbur Lam, MD, PhD, assistant professor in the Department of Pediatrics at Emory University School of Medicine and in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “Our device may function as a new physics-based method to test for bleeding disorders, complementary to current methods.”

The first author of the paper is instructor David Myers, PhD. Lam is also a physician in the Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta. Collaborators at North Carolina State University led by Ashley Brown, PhD, contributed to testing the device.

The scientists infer how strong or wimpy someone’s platelets are by measuring how far the protein dots move, taking a picture of the rows of dots, and then analyzing the picture on a computer. The dots are made of fibrinogen, a sticky protein that is the precursor for fibrin, which forms a mesh of insoluble strands in a blood clot.

In addition to detecting problems with platelet contraction in patients with known inherited disorders such as Wiskott Aldrich syndrome, Myers, Lam and colleagues could also see differences in some patients who had bleeding symptoms, but who performed normally on standard diagnostic tests. Read more

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Tapping evolution to improve biotech products

Scientists can improve protein-based drugs by reaching into the evolutionary past, a paper published this week in Nature Biotechnology proposes.

As a proof of concept for this approach, the research team from Emory, Children’s Healthcare of Atlanta and Georgia Tech showed how “ancestral sequence reconstruction” or ASR can guide engineering of the blood clotting protein known as factor VIII, which is deficient in the inherited disorder hemophilia A.

fviii_2r7e

Structure of Factor VIII

Other common protein-based drugs include monoclonal antibodies, insulin, human growth hormone and white blood cell stimulating factors given to cancer patients. The authors say that ASR-based engineering could be applied to other recombinant proteins produced outside the human body, as well as gene therapy.

It has been possible to produce human factor VIII in recombinant form since the early 1990s. However, current factor VIII products still have problems: they don’t last long in the blood, they frequently stimulate immune responses in the recipient, and they are difficult and costly to manufacture.

Experimental hematologist and gene therapist Chris Doering, PhD and his colleagues already had some success in addressing these challenges by filling in some of the sequence of human factor VIII with the same protein from pigs.

“We hypothesized that human factor VIII has evolved to be short lived in the blood to reduce the risk of thrombosis,” Doering says. “And we reasoned that by going even farther back in evolutionary history, it should be possible to find more stable, potent relatives.”

Doering is associate professor of pediatrics at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. The first author of the paper is former Molecular and Systems Pharmacology graduate student Philip Zakas, PhD.

Doering’s lab teamed up with Trent Spencer, PhD, director of cell and gene therapy for the Aflac Cancer and Blood Disorders Center, and Eric Gaucher, PhD, associate professor of biological sciences at Georgia Tech, who specializes in ASR. (Gaucher has also worked with Emory biochemist Eric Ortlund – related item on ASR from Gaucher)

ASR involves reaping the recent harvest of genome sequences from animals as varied as mice, cows, goats, whales, dogs, cats, horses, bats and elephants. Using this information, scientists reconstruct a plausible ancestral sequence for a protein in early mammals. They then tweak the human protein, one amino acid building block at a time, toward the ancestral sequence to see what kinds of effects the changes could have. Read more

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Bile acid uptake inhibitor prevents NASH/fatty liver in mice

Drugs that interfere with bile acid recycling can prevent several aspects of NASH (nonalcoholic steatohepatitis) in mice fed a high-fat diet, scientists from Emory University School of Medicine and Children’s Healthcare of Atlanta have shown.

The findings suggest that these drugs, known as ASBT inhibitors, could be a viable clinical strategy to address NASH, an increasingly common liver disease. The results were published in Science Translational Medicine on September 21, 2016.

“By targeting a process that takes place in the intestine, we can improve liver function and reduce insulin resistance in a mouse model of NASH,” says senior author Saul Karpen, MD, PhD. “We can even get fat levels in the liver down to what we see in mice fed a regular diet. These are promising results that need additional confirmation in human clinical trials.”

Karpen is Raymond F. Schinazi distinguished professor of pediatrics at Emory University School of Medicine and chief of the Division of Pediatric Gastroenterology, Hepatology and Nutrition at Children’s Healthcare of Atlanta. He and Paul Dawson, PhD, Emory professor of pediatrics, jointly run a lab that investigates the role of bile acids in liver disease.

Saul Karpen, MD, PhD

Saul Karpen, MD, PhD

Many people in developed countries have non-alcoholic fatty liver disease, an accumulation of fat in the liver that is linked to diet and obesity. Fatty liver disease confers an elevated risk of type II diabetes and heart disease. NASH is a more severe inflammation of the liver that can progress to cirrhosis, and is a rising indication for liver transplant. Besides diet and exercise, there are no medical treatments for NASH, which affects an estimated 2 to 5 percent of Americans. Read more

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Leaky gut plus diet together drive liver disease

 

Frank Anania, MD

Lots of people in the United States consume a diet that is high in sugar and fat, and many develop non-alcoholic fatty liver disease, a relatively innocuous condition. NASH (non-alcoholic steatohepatitis) is the more unruly version, linked to elevated risk of cardiovascular and metabolic diseases, and can progress to cirrhosis. NASH is expected to become the leading indication for liver transplant. But only a fraction of people with non-alcoholic fatty liver disease go on to develop NASH.

Thus, many researchers are trying to solve this equation:

High-sugar, high-fat diet plus X results in NASH.

Emory hepatologist Frank Anania and colleagues make the case in a recent Gastroenterology paper that a “leaky gut”, allowing intestinal microbes to promote liver inflammation, could be a missing X factor.

Anania’s lab started off with mice fed a diet high in saturated fat, fructose and cholesterol (in the figure, PrintHFCD). This combination gives the mice moderate fatty liver disease and metabolic syndrome (see this 2015 paper, and we can expect to hear more about this model soon from Saul Karpen). Leaky gut, brought about by removing a junction protein from intestinal cells, sped up and intensified the development of NASH.

The authors say that this model could be useful for the study of NASH, which has been difficult to reproduce in mice.

The researchers could attenuate liver disease in the mice by treatment with antibiotics or sevelamer, a phosphate binding polymer that soaks up inflammatory toxins from bacteria. Sevelamer is now used to treat excess phosphate in patients with chronic kidney disease, and is being studied clinically in connection with insulin resistance.
Read more

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Challenging long-held dogmas in cardiology

IGF1_heart

The growth factor IGF-1 (red) peaks roughly two days after an artificial heart attack in mice. But its levels are limited by an enzyme called chymase produced by mast cells. What if the influence of chymase could be curtailed?

Alert to science journalists looking for active debate: Emory cardiology researchers Nawazish Naqvi and Ahsan Husain are not afraid of controversy in their field.

In a 2014 Cell paper, they challenged the long-held assumption that after birth, cardiac muscle cells do not divide, showing a dramatic burst of thyroid hormone-driven cell division in the hearts of preadolescent mice. This finding has implications for regenerative medicine if it can be harnessed, but also stimulated a cluster of papers aiming to refute their findings in Cell the following year (and more are coming).

A second assumption that they’ve challenged more recently is that hours after a heart attack, endangered cardiac muscle cells can’t be rescued. Husain and Naqvi’s paper, published this week in PNAS, shows that the enzyme chymase — produced by a type of immune cell called mast cells — limits the heart’s ability to heal itself. Critically, differences in the extent of damage seen in mice lacking chymase and controls show up days after an artificial heart attack. More here.

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Rep. Tom Price discusses research funding

Rep. Tom Price (R-GA) expressed support for strong federal funding of scientific and biomedical research in a town-hall-type meeting Wednesday with Emory faculty and students, organized by the graduate student group Emory Science Advocacy Network.

Price tied a major expansion of federal funding for scientific research to reform of entitlements such as Medicare and Social Security (like this). Asked whether he could envision a large increase in the National Institutes of Health budget, comparable to the doubling in funding that occurred in the 1990s, Price replied: “In the near term, I don’t see it.”

However, a “smaller bump,” more along the lines of the $2 billion increase in NIH funding passed by Congress in December, could be more possible, he said.

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Price with Emory Science Advocacy Network officers/members

Price also advocated streamlining the Food and Drug Administration’s approval processes for new antibiotics and medical devices, and giving scientists more discretion in how federal research dollars are allocated.

In a question-and-answer session, Emory ethnobotanist Cassandra Quave urged Price to have Congress give increased attention to the problem of antibiotic resistance, in which some bacterial infections are becoming difficult to treat.

“Yes, we need more resources going into this,” Price said, going on to support a “dual track” approval process for new antibiotics.

Price expressed concerns that the United States’ role as a leader in medical innovation was waning, because of regulatory constraints that drive devices such as heart valves to be tested elsewhere first.

“We’re already losing bright minds,” he said, citing how colleagues from other surgical specialties were visiting other countries to learn new techniques.

Price, who represents parts of Cobb, Dekalb and Fulton counties, was appointed chairman of the House Budget Committee at the end of 2014, replacing Rep. Paul Ryan (R-WI).

Before his election to Congress in 2004, Price was an orthopedic surgeon. He grew up and went to medical school in Michigan, and came to Georgia for his orthopedic surgery residency at Emory. He was an assistant professor at Emory and medical director of the Orthopedic Clinic at Grady Memorial Hospital, while he was a member of the State Senate. Read more

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Please vote in Best Image contest

Emory University School of Medicine’s Office of Postdoctoral Education has posted ten dazzling images from current Emory biomedical research here, and you can vote on your favorites (VOTE HERE). The Best Image contest sets the stage for the Postdoctoral Research Symposium on May 19. A gallery showing all ten at once — larger than what you see below– is also available at this site.

Voting lasts only until Sunday (4/23), since the three contest-winning images will be part of the abstract book and other materials, and the organizers need to complete printing orders soon.Screen Shot 2016-04-19 at 12.46.17 PM

Lab Land is looking forward to learning more about the images. For now, it is fun to guess what they are. In the gallery, each one is labeled with the name of the researcher who submitted them. Read more

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Manipulating mouse genes to order, CRISPR or old-school

Just a follow-up to last week’s announcement from the Emory Transgenic Mouse and Gene Targeting core that they are offering CRISPR/Cas9 gene editing for mice. Using CRISPR/Cas9 to produce genetically altered mice is a

Knockout_mice

Gene targeting – the 20th century way

substantial advance over the old way of doing knockouts and other manipulations (which itself won a Nobel Prize in 2007), mainly because it’s faster and easier.

To appreciate the difference, consider that the old way involves introducing DNA into mouse embryonic stem cells, and then selecting for the rare cells that take up and incorporate the DNA in the right way. Then the ES cells have to be injected into a blastocyst, followed by mouse breeding to “go germline.”

With CRISPR/Cas9, it’s possible to inject pieces of RNA that target the desired genetic changes, straight into a one-cell stage mouse embryo. Not every embryo has all the right changes, but the frequency is high enough to inject and screen. As this review explains, it’s possible to introduce mutations into three genes at once and get mice quickly, rather than make each one separately and then breed the mice together, which can take many months.

Also, because of the need for drug selection, the targeting construct in old-school gene targeting has to be a blunt instrument. That can make it hard to make subtle changes to a gene — like introduce point mutations corresponding to natural variations linked with human disease — without taking a sledgehammer to the entire gene locus. CRISPR/Cas9 takes care of that problem.

Despite the advantages of this technology, three things to keep in mind:

*Many genetically altered mice are already available “off the shelf” as part of the International Knockout Mouse/Mouse Phenotyping Consortium.

*Emory’s Mouse Core has been working with the company Ingenious Gene Targeting, and has been out-sourcing some of the tedious aspects of old-school gene targeting in mice to Ingenious, starting last year. Technicians there can generate a dazzling array of conditional knockouts. If you want your favorite gene to flip around and produce a fluorescent protein when you give the mice an antibiotic, but only in some cells — Ingenious can do that. Old school is actually still the way to go for fancy stuff like this.

*Jackson Labs in Maine also works with Emory, offering similar services, and offers a guarantee. Read more

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