Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more
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Immunology

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

Posted on September 29, 2016 by Quinn Eastman in Immunology, Uncategorized Leave a comment

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

Posted on September 22, 2016 by Quinn Eastman in Uncategorized Leave a comment

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

Posted on August 29, 2016 by Quinn Eastman in Uncategorized Leave a comment

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.

Posted on June 9, 2016 by Quinn Eastman in Uncategorized Leave a comment

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

Posted on May 5, 2016 by Quinn Eastman in Uncategorized Leave a comment

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

Posted on April 19, 2016 by Quinn Eastman in Uncategorized Leave a comment

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

Posted on March 30, 2016 by Quinn Eastman in Uncategorized Leave a comment

Measuring microbiome disruption

How should doctors measure how messed up someone’s intestinal microbiome is?

This is the topic of a recent paper in American Journal of Infection Control from Colleen Kraft and colleagues from Emory and the Centers for Disease Control and Prevention. The corresponding author is epidemiologist Alison Laufer Halpin at the CDC.

A “microbiome disruption index” could inform decisions on antibiotic stewardship, where a patient should be treated or interventions such as fecal microbial transplant (link to 2014 Emory Medicine article) or oral probiotic capsules.

What the authors are moving towards is similar to Shannon’s index, which ecologists use to measure diversity of species. Another way to think about it is like the Gini coefficient, a measure of economic inequality in a country. If there are many kinds of bacteria living in someone’s body, the disruption index should be low. If there is just one dominant type of bacteria, the disruption index should be high.

In the paper, the authors examined samples from eight patients in a long-term acute care hospital (Wesley Woods) who had recently developed diarrhea. Using DNA sequencing, they determined what types of bacteria were present in patients’ stool. The patients’ samples were compared with those from two fecal microbial transplant donors. Read more

Posted on March 21, 2016 by Quinn Eastman in Immunology, Uncategorized Leave a comment

Beyond CF – potential byproducts of precision medicine

Just a quick comment on the potential of research being conducted by Eric Sorscher, who came to Emory from University of Alabama, Birmingham in 2015 and is now a Georgia Research Alliance Eminent Scholar. While Sorscher’s lab is working on advancing new treatments for cystic fibrosis patients who currently do not benefit from available drugs, it was intriguing to learn of potential side benefits beyond cystic fibrosis.

Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a protein with important functions in cells that produce mucus, sweat, saliva, tears and digestive enzymes. But other things can impair the functioning of the CFTR protein besides genetic mutations. Namely, smoking. Read more

Posted on February 22, 2016 by Quinn Eastman in Uncategorized Leave a comment

From Emory scientist to California policy analyst

Don’t call them alternative careers — since most graduate students in the biomedical sciences won’t end up as professors. Since I found a career outside the laboratory myself, I like to keep an eye out for examples of Emory people who have made a similar jump. [Several more in this Emory Magazine feature, which mentions the BEST program, aimed at facilitating that leap.]

Debra Cooper, PhD

Debra Cooper, PhD

After a postdoc in Texas, former Emory neuroscience graduate student Debra Cooper was awarded a California Council on Science and Technology fellowship to work with the California State Senate staff, and is now a policy consultant there. More about her work can also be found at the CCST blog.

Describe your position as policy consultant now. What types of things do you work on? How does your experience in neuroscience/drug abuse research fit in?

As a policy consultant at the California State Senate Office of Research, I function as a bridge between policy and the technical information that informs public policy. A large component of my time is spent translating research and linking it with relevant policies and regulations. I then synthesize this information and disseminate it to the appropriate audiences through memoranda, reports, or presentations. Sometimes this information is used to advise and make recommendations for legislative ideas.

My main assignments deal with human services (i.e., public services provided by governmental organizations) and veterans affairs. As such, not every project that I work on is directly related to neuroscience, but I often find overlap between my assignments and my academic background. For instance, the intersection of mental health and veterans affairs services is an important topic that bridges my backgrounds. Even when I’m working on issues that don’t directly link to mental health, the years that I spent analyzing research and statistics comes in handy when evaluating relevant documents.

Describe your graduate research at Emory.

I had co-advisors while working on my PhD at Emory – Drs. David Weinshenker and Leonard Howell. My dissertation research focused on one question answered with two different model animals: rats (Weinshenker lab) and squirrel monkeys (Howell lab, click here to know learn more about the scales that are available in the lab). I was studying the effectiveness of a drug, nepicastat, in reducing rates of relapse to cocaine abuse. Nepicastat blocks an enzyme (dopamine beta-hydoxylase) which is crucial for converting the neurochemical dopamine into the neurochemical norepinephrine. Both of these neurochemicals are involved in responses to cocaine, and we hypothesized that nepicastat could help in regulating these neurochemicals to prevent relapse. Read more

Posted on February 19, 2016 by Quinn Eastman in Neuro, Uncategorized Leave a comment
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