Nox-ious link to cancer Warburg effect

Invitation from a talk by San Martin recently gave in Read more

Viral vectors ready for delivery

The phrase “viral vector” sounds ominous, like something from a movie about spies and Internet intrigue. It refers to a practical delivery system for the gene of your Read more

Exotic immune systems are big business

Research on lampreys’ variable lymphocyte receptors may seem impractical. Good examples exist of weird animals' immune systems becoming big Read more

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Five hot projects at Emory in 2017

CRISPR-Cas9 gene editing alleviates Huntington’s in mouse model

— Shi-Hua and Xiao-Jiang Li. This project is progressing, with funding from NCATS and a pig-oriented collaboration with partners in China.

Once activated by cancer immunotherapy drugs, T cells still need fuel (CD28)

— Rafi Ahmed’s lab at Emory Vaccine Center. Also see T cell revival predicts lung cancer outcomes. At Thursday’s Winship symposium on cancer immunotherapy, Rafi said the name of the game is now combinations, with an especially good one being PD-1 inhibitors plus IL2.

Pilot study shows direct amygdala stimulation can enhance human memory

— Cory Inman, Joe Manns, Jon Willie. Effects being optimized, see SFN abstract.

Immune responses of five returning travelers infected by Zika virus

— Lilin Lai, Mark Mulligan. Covered here, Emory Hope Clinic and Baylor have data from more patients.

Frog slime kills flu virus

— Joshy Jacob’s lab at Emory Vaccine Center. A follow-up peptide with a name referencing Star Wars is coming.

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Shaking up thermostable proteins

Imagine a shaker table, where kids can assemble a structure out of LEGO bricks and then subject it to a simulated earthquake. The objective is to design the most stable structure.

Biochemists face a similar task when they are attempting to design thermostable proteins, with heat analogous to shaking. Thermostable proteins, which do not become unfolded/denatured at high temperatures, are valuable for industrial processes.

Now imagine that these stable structures have to also perform a function. This is the two-part challenge of designing thermostable proteins. They have to maintain their physical structure, and continue to perform their function adequately, all at high temperatures. 

Eric Ortlund and colleagues, working with Eric Gaucher at Georgia Tech*, have a new paper published in Structure, in which they examine different ways to achieve this goal in a component of the protein synthesis machinery, EF-Tu. This protein exists in both mesophilic bacteria, which live at around human body temperature, and thermophilic organisms (think: hot springs).

A previous analysis by Gaucher used the ASR technique (ancestral sequence reconstruction) to resurrect ancient, extinct EF-Tus and characterize them. It was shown that that ancestral EF-Tus were thermostable and functional. EF-Tu’s thermostability declined along with the environmental temperature; ancestral bacteria started off living in hot environments and those environments cooled off over millions of years.

In the new paper, Ortlund and first author Denise Okafor show that stable proteins generated by protein engineering methods do not always retain their functional capabilities. However, the ASR technique has a unique advantage, Ortlund says. By accounting for the evolutionary history of the protein, it preserves the natural motions required for normal protein function. Their results suggest that ASR could be used to engineer thermostability in other proteins besides EF-Tu.

*Gaucher recently moved to Georgia State.

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A push for reproducibility in biomedical research

Editor’s note: guest post from Neuroscience graduate student Erica Landis.

Neuroscience graduate student Erica Landis

Evidence is increasing that lack of reproducibility, whatever the cause, is a systemic problem in biomedical science. While institutions like the NIH and concerned journal editors are making efforts to implement more stringent requirements for rigorous and reproducible research, scientists themselves must make conscious efforts to avoid common pitfalls of scientific research. Here at Emory, several scientists are making greater efforts to push forward to improve scientific research and combat what is being called “the reproducibility crisis.”

In 2012, C. Glenn Begley, then a scientist with the pharmaceutical company Amgen, published a commentary in Nature on his growing concern for the reproducibility of preclinical research. Begley and his colleagues had attempted to replicate 53 published studies they identified as relevant to their own research into potential pharmaceuticals. They found that only 6 of the 53 publications could be replicated; even with help from the original authors. Similar studies have consistently found that greater than 50 percent of published studies could not be replicated. This sparked a period of great concern and questioning for scientists. It seemed to Begley and others that experimenter bias, carelessness, poor understanding of statistics, and the career-dependent scramble to publish contributes to a misuse of the scientific method. These factors contribute to what is now called the reproducibility crisis. In April 2017, Richard Harris published Rigor Mortis, a survey of the problem in preclinical research, which has kept the conversation going and left many wondering what the best solution to these issues could be. To combat the reproducibility crisis, Harris argues that funding agencies, journal editors and reviewers, research institutions, and scientists themselves all have a role to play.

Read more

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New pediatric digestive/liver disease gene identified by international team

In a study published this month in Hepatology, a multinational team of researchers describes a newly identified cause of congenital diarrhea and liver disease in children.

The rare disorder is characterized by significant diarrhea beginning soon after birth, low serum levels of fat-soluble vitamins and evidence of liver disease. Despite continued symptoms, with medical support, the children grow and develop normally, at least to the age of 12.

From left to right: Mutaz Sultan, Orly Elpeleg and Paul Dawson, representing three collaborating institutions.

Researchers from Emory University School of Medicine and Children’s Healthcare of Atlanta, working with colleagues from Makassed Hospital, Al-Quds University and Hadassah Medical Center, Hebrew University of Jerusalem studied a family with two children from the Palestinian territories who suffer from the disorder.

The team found that both children had inherited a mutation in a gene responsible for the transport of bile acids, which facilitate the digestion and absorption of dietary fats and fat-soluble vitamins. Although mutations had been identified in other genes important for the recycling of bile acids, this is the first report in humans of disease-associated defects in this gene, called Organic Solute Transporter-beta (SLC51B).

Almost 20 years ago, pediatric GI & hepatology researcher Paul Dawson, PhD, and colleagues identified mutations in another bile acid transporter gene (ASBT; SLC10A2) that caused congenital bile acid diarrhea.

“Even at that time, we knew that there were patients with similar symptoms that did not carry mutations in ASBT. But the genetic cause remained a mystery.” Dawson says. “What’s distinctive about this report is that these patients also have features of liver disease, which was not observed in previously described congenital bile acid diarrhea patients.” Read more

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IMSD program nurtures young scientists

Guest post from Megan McCall, who works at Winship Cancer Institute. Thanks Megan!

On a Thursday afternoon this past semester, a diverse group of 50 students were listening to a lecture on the art of storytelling by Eladio Abreu, a lecturer in the Biology department. This was an unusual topic for these students, but they sat enrapt, not distracted by cell phones or laptops.

Eladio Abreu, PhD

The weekly seminar was part of the Emory Initiative to Maximize Student Development (IMSD) program, aimed at the professional development of undergraduate and graduate students in STEM fields. What sets this program apart is its commitment to increase diversity in the biological, biomedical and behavioral sciences by nurturing students who may be underrepresented in these fields. IMSD’s associate director Amanda James says the program includes some of Emory’s strongest students.

The two-year, NIH-funded research program has three main goals: preparing undergraduate students for doctoral programs in STEM fields, nurturing graduate students during their matriculation into Emory’s Ph.D. programs and increasing diversity through mentoring. They accomplish these goals by connecting undergraduates and graduates through mentorship, seminars, and career coaching, says Keith Wilkinson, IMSD director and vice-chair of the Department of Biochemistry.

(from left) Lina Jowhar, Max Cornely, Chayla Vazquez, and Jamie Guillen at an Initiative to Maximize Student development meeting.

This meeting included updates from students on their summer research plans. Answers ranged from epidemiology research with a children’s hospital in Philadelphia, to influenza research at Johns Hopkins. In addition to weekly seminars, IMSD offers classes aimed at increasing success post-graduation, workshops for career development, and pathways to funded research, a rare commodity for undergraduates. Students who can’t do funded research may use resources that IMSD offers to find other opportunities.

Lina Jowhar is an undergraduate who started the program in her third year at Emory. She is engaged in research on cystic fibrosis, a genetic disorder of the lungs, and she values the weekly meetings, particularly Abreu’s lecture on the art of storytelling. “I love his interactive teaching style,” she says. “He was comfortable letting us know that he changed the examples in his PowerPoint to include Biggie and Tupac which showed me how important it is to connect with your audience.” Read more

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NGLY1 update

Emory Medicine readers may remember the Stinchcombs, a Georgia family caring for two daughters with a genetic neurological/developmental disorder called NGLY1 deficiency. We found their efforts to care for their daughters inspiring.

The rapid discovery of several children with NGLY1 deficiency, facilitated by social media, has led to a wave of research. Two recent papers represent advances toward finding treatments.

In PLOS Genetics, Japanese scientists showed that deleting the ENGase gene can partially rescue problems created by NGLY1 deficiency in a mouse model (RIKEN press release). That implies drugs that inhibit the ENGase enzyme might have similar positive effects.

Scientists knew that the NGLY1 enzyme removes chains of sugars from misfolded proteins that are stalled in cells’ production pipeline. ENGase is another enzyme that acts on those sugar chains, and its absence compensates for the lack of NGLY1. Read more

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March for Science ATL: photos

Emory scientists and supporters of science were out in substantial numbers Saturday at the March for Science Atlanta in Candler Park.

March organizers, many of whom came from the Emory research community, say they want to continue their advocacy momentum and community-building after the event’s success. Check out the web site “Science Marches On” for post-march activities. The organizers have estimated that somewhere around 8,000 people participated in Saturday’s march, based on aerial drone footage and Atlanta Police estimates.

Marchers Jarred Whitlock, Bethany Whitlock, Erica Werner, Victor Faundez, and Chelsea Lee (left to right)

Several issues propelled the Marches for Science around the world: proposed research funding reductions, skepticism on specific issues such as climate change or vaccines, and attention on diversity in science. Some Emory folks such as autism geneticist/communicator Chris Gunter and oncology nursing leader Deborah Bruner were in Washington DC for the March for Science there.

Here in Atlanta, marchers had a variety of colorful costumes and signs, with messages ranging from the blunt to the subtle.  The crowds enjoyed sunny weather and pre-march entertainment from the punk rock band Leucine Zipper and the Zinc Fingers.

Former Emory neuroscience postdoc Alison Bernstein, who blogs as “Mommy PhD” and is now an assistant professor at Michigan State, was one of the first speakers, describing how some vaccine skeptics have embraced unproven and possibly dangerous treatments for conditions such as eczema.

Emory virologist Anice Lowen was quoted in this WABE story.

Read more

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How race + TBI experience affect views of informed consent

The upcoming HBO movie of The Immortal Life of Henrietta Lacks reminds us that biomedical research has a complex legacy, when it comes to informed consent and people of color.

A paper from Emory investigators, published in AJOB Empirical Bioethicstouches on related current issues. The paper examines how race and close experience with traumatic brain injury affect study participants’ views of informed consent in clinical research.

This emerged from a study of community consultation for EFIC (exception from informed consent), in connection with a nationwide clinical trial of progesterone for traumatic brain injury (TBI). EFIC describes clinical research performed when the normal process of obtaining patients’ informed consent is not possible, because of emergency conditions such as seizures or TBI. Before such studies can be undertaken, the FDA calls for protective procedures and community consultation.

In this case, researchers surveyed 2612 people at 12 sites involved in the TBI study. The survey asked about attitudes toward the EFIC aspects of the study and also asked if they had personal experience with traumatic brain injury – either themselves or someone close to them. How that personal connection affected their responses was influenced by race.

Key paragraph from discussion:

Among white participants, increased levels of acceptance of EFIC were found among those with any connections to TBI. On the other hand, among participants identifying as black or other nonwhite races, there was decreased acceptance of EFIC enrollment among TBI patients and no increase in acceptance among those with a family member/loved one with TBI. The fact that black and white participants with no personal TBI experience or with a more distant connection to TBI had similar acceptance rates suggests that baseline acceptance of EFIC among these two groups is fairly similar and that the experience with the condition itself plays a role in driving the observed differences…

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Fecal transplant replants microbial garden

When facing a life-threatening infection, the “yuck factor” is a minor concern. Fecal microbiota transplant (FMT for short) has become an accepted treatment for recurrent Clostridium difficile infection, which can cause severe diarrhea and intestinal inflammation.

In a new video, Emory physicians Colleen Kraft and Tanvi Dhere explain how FMT restores microbial balance when someone’s internal garden has been disrupted.

C. difficile or “C diff” is a hardy bacterium that can barge into the intestines after another infection has been treated with antibiotics, when competition for real estate is low. In the last few years, doctors around the world have shown that FMT can resolve recurrent C diff infection better than antibiotics alone.

At Emory, Kraft and Dhere have performed almost 300 FMTs and report a 95 percent success rate when treating recurrent C diff. They have established a standard slate of stool donors, whose health is carefully screened.

Building on their experience with the procedure, Kraft and Dhere are studying whether FMT can head off other antibiotic-resistant infections besides C diff in kidney transplant patients. They have teamed up with infectious disease specialists Aneesh Mehta and Rachel Friedman-Moraco to conduct this study. Read more

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The very first cells

Please welcome cell biologist Dorothy Lerit to Emory.

Dorothy Lerit, PhD

She was the lead author on a recent Cell Reports paper on primordial germ cell formation in Drosophila, along with colleagues from NHLBI, where she was a postdoc, as well as Princeton, UVA and Columbia. Primordial germ cells are the cells that are destined to become sperm or eggs.

Germ cells are the very first cells that form out of the embryo, Lerit says. Lab Land is reminded of Lewis Wolpert’s claim that gastrulation – the separation of an apparently uniform group of embryonic cells into three germ layers — is “truly the most important time in your life.” Germ cell specification, certainly important from the viewpoint of future generations, occurs even before gastrulation.

In the Cell Reports paper, Lerit was examining the function of a particular gene called Germ cell-less; remember that Drosophila genes are often named after the effects of a mutation in the gene.

Drosophila development is superficially quite different from that of mammals. In particular, for a while the early embryo becomes a bag full of cell nuclei — without membranes separating them — known as a syncytium. This is the time when Germ cell-less function is important.

Amazing picture of germ cell formation from HHMI/Nature Cell Biology/Ruth Lehmann’s lab https://www.hhmi.org/node/16760/devel

Lerit’s background is in studying the centrosome, the place in the cell where microtubules meet, and critical for orderly cell division and for ensuring that “germline fate determinants” are sequestered to the right primordial cells.

Despite the differences between insect and mammalian embryo development, the function of Germ cell-less seems to have been conserved in evolution since problems with the human version of the gene are linked to sterility in men.

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