Burning fat like a baby

Newborn humans and hibernating mammals have high levels of brown adipose tissue, which they use to generate heat. Adult humans generally don’t have abundant brown adipose tissue, even if they have lots of “white” fat. Increasing brown fat’s activity may be an approach to treat obesity and related metabolic disorders.

Recently researchers identified an enzyme called Them1 (thioesterase superfamily member 1) as a factor that limits heat generation in brown adipose tissue. Emory biochemist Eric Ortlund and his lab showed how part of the Them1 enzyme binds a certain type of lipid molecule, and also how that part of the enzyme anchors the enzyme close to lipid droplets in adipose cells. Former graduate student Matt Tillman, now a postdoc at Duke, was the first author of the new paper in Proceedings of the National Academy of Sciences.

“In this study, we show Them1 contains a lipid sensor module that detects specific lipids within the cell to regulate its activity,” says Tillman.

In brown adipose cells, the lipid-sensing domain of Them1 is needed for localization around lipid droplets

From Tillman et al PNAS (2020)

He and his colleagues showed that a lipid known for its role in cell signaling, lysophosphatidylcholine or LPC, inhibits Them1 activity, which in turn activates thermogenesis in brown adipose tissue. In contrast, other fatty acids that serve as fuel tend to activate Them1. This regulatory system within Them1 allows the cell to sense its metabolic state and decide when to burn or conserve fat.

Posted on August 21, 2020 by Quinn Eastman in Uncategorized Leave a comment

Triple play in science communication

Emory BCDB graduate student Emma D’Agostino

We are highlighting Emory BCDB graduate student Emma D’Agostino, who is a rare triple play in the realm of science communication.

Emma has her own blog, where she talks about what it’s like to have cystic fibrosis. Recent posts have discussed the science of the disease and how she makes complicated treatment decisions together with her doctors. She’s an advisor to the Cystic Fibrosis Foundation on patient safety, communicating research and including the CF community in the research process. She’s also working in biochemist Eric Ortlund’s lab on nuclear receptors in the liver:drug targets for the treatment of diabetes and intestinal diseases.

The triple play is this — on her blog, Emma has discussed how she has to deal with antibiotic resistance. Emory Antibiotic Resistance Center director David Weiss’ lab has published a lot on colistin: how it’s a last-resort drug because of side effects, and how difficult-to-detect resistance to it is spreading. Emma has some personal experience with colistin that for me, brought the issue closer. Read more

Posted on July 20, 2020 by Quinn Eastman in Uncategorized Leave a comment

Emory plays leading role in landmark HIV prevention study of injectable long-acting cabotegravir

Emory University played a key role in a landmark international study evaluating the safety and efficacy of the long-acting, injectable drug, cabotegravir (CAB LA), for HIV prevention.

The randomized, controlled, double-blind study found that cabotegravir was 69% more effective (95% CI 41%-84%) in preventing HIV acquisition in men who have sex with men (MSM) and transgender women who have sex with men when compared to the current standard of care, daily oral emtricitabine/tenofovir disoproxil fumarate 200 mg and 300 mg (FTC/TDF) tablets.

The study achieved its primary objective of non-inferiority with the difference approaching superiority in favor of cabotegravir, pending final analysis.

The findings were so positive that, during a planned review of study data, an independent Data and Safety Monitoring Board (DSMB) recommended the study results be announced as soon as possible. The study sponsor, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, agreed with that recommendation.

Emory, through the Emory-CDC HIV Clinical Trials Unit, enrolled 7% of the study’s more than 4,500 worldwide participants at three of its clinical research sites: The Hope Clinic (86 participants) and the Ponce de Leon Center (35 participants) in Atlanta and at the CDC’s Silom Community Clinic in Bangkok, Thailand (203 participants).

“This is a landmark study with a new approach that will change how HIV prevention is being done and will open the field to future interventions,” says Carlos del Rio, MD, the executive associate dean, Emory University School of Medicine at Grady Health System. Del Rio is a member of the study team and the principal investigator at the Ponce de Leon Center.

Posted on May 28, 2020 by Wayne Drash in Uncategorized Leave a comment

‘Genetic doppelgangers:’ Emory research provides insight into two neurological puzzles

An international team led by Emory scientists has gained insight into the pathological mechanisms behind two devastating neurodegenerative diseases. The scientists compared the most common inherited form of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) with a rarer disease called spinocerebellar ataxia type 36 (SCA 36).

Both of the diseases are caused by abnormally expanded and strikingly similar DNA repeats. However, ALS progresses quickly, typically killing patients within a year or two, while the disease progression of SCA36 proceeds more slowly over the course of decades. In ALS/FTD it appears that protein products can poison cells in the nervous system. Whether similar protein products exist in SCA36 is not known.

What Zachary McEachin, PhD, and Gary Bassell, PhD, from Emory’s Department of Cell Biology, along with a team of collaborators at Emory, the Mayo Clinic in Jacksonville, Florida, and internationally from Spain and Japan, discovered have provided a new paradigm for thinking about how aberrant protein species are formed. Regardless of the disparate clinical outcomes between these diseases, this research could broaden the avenue of research toward genetically targeted treatments for such related neurodegenerative diseases.

Their study, published Tuesday in Neuron, provides a guide to types of protein that build up in brain cells in both disorders, and which should be reduced if the new mode of treatment is working in clinical trials.

“We are thinking of these diseases as genetic doppelgängers,” says McEachin, a postdoctoral fellow in Bassell’s lab. “By that, I mean they are genetically similar, but the neurodegeneration progresses differently for each disease. We can use this research to understand each of the respective disorders much better — and hopefully help patients improve their quality of life down the road with better treatments.”

An estimated 16,000 people in the United States have ALS, a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. The most common inherited form of ALS/FTD occurs because there is an abnormally expanded repeat of six DNA “letters” stuck into a gene called c9orf72.

Posted on May 5, 2020 by Wayne Drash in Neuro, Uncategorized Leave a comment

Emory launches study on COVID-19 immune responses

Emory University researchers are taking part in a multi-site study across the United States to track the immune responses of people hospitalized with COVID-19 that will help inform how the disease progresses and potentially identify new ways to treat it. The study is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The study – called Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) – launched Friday. Investigators expect to enroll up to 2,000 individuals who have been hospitalized with the new coronavirus in 10 research locations across the country.

Participants will be followed for up to 12 months after their hospitalization to assess how well they recover and whether they develop durable immunity to the virus.

Nadine Rouphael, associate professor at Emory’s School of Medicine, is leading the investigation as part of NIAID’s Human Immunology Project Consortium (HIPC) and says the study aims to determine how certain immunological measures correspond to or even predict the clinical severity of COVID-19.

“The IMPACC study is a unique opportunity to leverage clinical data and samples with cutting edge technology,” Rouphael says. “By analyzing the immune responses of diverse participants enrolled in the study, we aim to better understand why some cases of COVID-19 worsen while other patients recover.”

As participants recover, investigators will continue evaluating their immune responses to see how they fare: Do they experience lingering symptoms, or do they get long-term protection against the virus? This effort is one of many clinical projects working to better understand how this novel disease affects people differently and determine optimal ways to treat COVID-19.

Researchers will recruit participants within 36 hours of their admission to the hospital and collect blood and nasal swabs throughout their hospitalization, and during follow-up clinic visits after discharge. When possible, researchers will also examine lower airway secretions collected from patients requiring a ventilator for breathing support. Participants can be co-enrolled in other studies, such as those evaluating experimental treatments for COVID-19.

Biologic samples from all study participants will be sent to a number of Core Laboratories for detailed analysis of various aspects of the immune response to the virus that causes COVID-19.

For more information on the U.S. government response to the COVID-19 pandemic, visit www.coronavirus.gov.

Posted on May 1, 2020 by Wayne Drash in Immunology, Uncategorized Leave a comment

Marcus Lab researchers make key cancer discovery

A new discovery by Emory researchers in certain lung cancer patients could help improve patient outcomes before the cancer metastasizes.

The researchers in the renowned Marcus Laboratory identified that highly invasive leader cells have a specific cluster of mutations that are also found in non-small cell lung cancer patients. Leader cells play a dominant role in tumor progression, and the researchers discovered that patients with the mutations experienced poorer survival rates.

The findings mark the first leader cell mutation signature identified in patients and could prove key in teasing out high-risk patients, allowing oncologists to develop a treatment plan early on before the disease has progressed.

“It has been a lot of fun to see the research go from the basic science side inside the lab to hopefully having an actual clinical impact,” says Brian Pedro, an MD/PhD student in Emory’s Medical Scientist Training Program. “Our data suggest that if you have one or more of these mutations, then we could potentially intervene early and improve patient outcomes.”

Stopping leader cells before they metastasize has long been a goal of researchers at the Winship Cancer Institute. “That is what we strive for as researchers,” Pedro says. “We are optimistic that this could be a promising clinical tool.”

The findings were published in the American Cancer Society’s journal “Cancer.”

The researchers specifically found the novel mutation cluster on chromosome 16q and compared the survival rates of those who had the mutations with those who did not. The results showed the patients who had the mutations had poorer survival rates across all stages.

Pedro says more investigation is needed to figure out why the mutations lead to poorer outcomes. He adds that he hopes the mutation signature can prove useful for cancer types beyond lung cancer.

You can learn more from Pedro’s Tweetstorm.

Excited to share our new paper, published online today @JournalCancer (https://t.co/Mo0VlAsjJY). Briefly, we found that mutations identified from invasive leader cells correlate with poor survival in non-small cell #lungcancer patients. For those interested, here’s a #tweetorial:

— Brian Pedro (@brian_pedro) April 22, 2020

Posted on April 28, 2020 by Wayne Drash in Cancer, Uncategorized Leave a comment

Super-cold technique = hot way to see enzyme structure

In the last decade, a revolution has been taking place in structural biology, the field in which scientists produce detailed maps of how enzymes and other machines in the cell work. That revolution is being driven by cryo-electron microscopy (cryo-EM for short), which is superseding X-ray crystallography as the main data-production technique and earned a chemistry Nobel in 2017.

Just before COVID-19 sent some Emory researchers home and drove others to pivot their work toward coronavirus, Lab Land had a chance to tour the cryo-EM facility and take photos, with the help of Puneet Juneja, director of the core. Juneja demonstrated how samples are prepared for data collection — see the series of photos below.

Someone coming into the facility in the Biochemistry Connector area will notice a sign telling visitors and those passing by to stay quiet (forgot to take a photo of that!). The facility has electrical shielding and temperature/humidity controls. Also two levels of cooling are required for samples, since they are flash-frozen or “vitrified” in liquid ethane, which is in turn cooled by liquid nitrogen. The cooling needs to happen quickly so that ice crystals do not form. The massive cryo-EM equipment rests on a vibration-reduction platform; no music and no loud conversation are allowed during data collection.

One of the first structures obtained in this relatively new facility was the structure of a viral RNA polymerase, the engine behind viral replication. It wasn’t a coronavirus enzyme – it was from RSV (respiratory syncytial virus).

Still, cryo-EM is a way to visualize exactly how drugs that inhibit the SARS-CoV-2 polymerase – such as remdesivir or Emory’s own EIDD-2801 – exert their effects. Chinese researchers recently published a cryo-EM structure of the SARS-CoV-2 polymerase with remdesivir in Science. Read more

Posted on April 13, 2020 by Quinn Eastman in Immunology, Uncategorized Leave a comment

Blog editor shift

This is partly a temporary good-bye and partly an introduction to Wayne Drash.

Wayne will be filling in for Quinn Eastman, who has been the main editor of Lab Land. Wayne is a capable writer. He spent 24 years at CNN, most recently within its health unit. He won an Emmy with Sanjay Gupta for a documentary about the separation surgery of two boys conjoined at the head.

Wayne plans to continue writing about biomedical research at Emory, both COVID-19-related and not. He and Quinn are particularly interested in the efforts of Emory physicians and immunologists to develop a convalescent plasma bank and serology testing, as well as the continued progress of the DRIVE antiviral. It has been inspiring to see the Emory research community rally against COVID-19, despite huge challenges. Read more

Posted on April 6, 2020 by Quinn Eastman in Uncategorized Leave a comment

Some types of intestinal bacteria protect the liver

Certain types of intestinal bacteria can help protect the liver from injuries such as alcohol or acetaminophen overdose, according to Emory scientists led by pathologist Andrew Neish and physiologist Dean Jones.

The research was published on March 25 in Cell Metabolism.

“The composition of the microbiota, because of natural variation, dysbiosis, or supplementation with probiotics, can strongly affect how the liver processes both toxins and pharmacological agents, and thus have clinical consequences on how individuals respond to such exogenous chemicals,” Neish says.

While pretreatment with bacteria is needed for the observed effect in acute liver injury, probiotics or small molecule substitutes may be useful in the treatment of chronic liver diseases, the authors suggest. There are legal experts that can help with injury cases even if it’s after a slip and fall injury.

In mice, oral administration of Lactobacillus rhamnosus or LGG could protect against liver damage brought on by alcohol or acetaminophen. Several labs had already observed a beneficial effect from LGG against liver injury, but the Emory research establishes an additional mechanism.

Certain medical emergencies require immediate first aid medical care and one can get trained at c2cfirstaidaquatics in North York and be certified at first aid.

The protection comes from a small molecule metabolite produced by the bacteria called 5-MIAA (5-methoxyindoleacetic acid), activating the mammalian transcription factor Nrf2. Other types of bacteria did not produce 5-MIAA or activate Nrf2. While LGG is also known to improve the barrier function of the gut and dampen inflammation, liver-specific depletion of Nrf2 prevented LGG’s beneficial effects, suggesting that this is the primary mechanism of action.

Posted on April 3, 2020 by Quinn Eastman in Uncategorized Leave a comment

Can blood from coronavirus survivors save the lives of others?

Donated blood from COVID-19 survivors could be an effective treatment in helping others fight the illness – and should be tested more broadly to see if it can “change the course of this pandemic,” two Emory pathologists say.

The idea of using a component of survivors’ donated blood, or “convalescent plasma,” is that antibodies from patients who have recovered can be used in other people to help them defend against coronavirus.

Emory pathologists John Roback, MD, PhD and Jeannette Guarner, MD, wrote about the prospects of using the donated blood in a commentary published in JAMA. Their article accompanied a small study in China of five patients on ventilators whose condition improved after they were treated with convalescent plasma.

“Deploying passive antibody therapies against the rapidly increasing number of COIVD-19 cases provides an unprecedented opportunity to perform clinical studies of the efficacy of this treatment against a viral agent,” the two wrote. “If the results of rigorously conducted investigations, such as a large-scale randomized clinical trial, demonstrate efficacy, use of this therapy also could help change the course of this pandemic.”

The patients in Shenzhen were also treated with other antiviral and antiinflammatory agents, and the study was too small to come to definite conclusions. Still, the Emory authors say, the Shenzhen study provides an example of an approach that should be tested on a larger scale. Read more

Posted on March 31, 2020 by Wayne Drash in Immunology, Uncategorized Leave a comment

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