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
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
A study from Winship Cancer Institute of Emory University has the potential to change how patients whose prostate cancer recurs after prostatectomy are treated. The study was featured in both the plenary session and press program of the American Society for Radiation Oncology (ASTRO) Annual Meeting on Monday, October 26.
The Emory Molecular Prostate Imaging for Radiotherapy Enhancement, or EMPIRE-1 trial (NCT01666808), is the first randomized trial of men with prostate cancer with recurring cancer to show that treatment based on advanced molecular imaging can improve disease-free survival rates. The molecular imaging used in the study, the radiotracer fluciclovine (18F) PET, was invented and developed at Emory and Winship.
The phase II/III trial was led by Winship radiation oncologist and prostate cancer specialist Ashesh B. Jani, MD, MSEE, FASTRO, and Winship nuclear radiology specialist David M. Schuster, MD, FACR. The trial enrolled 165 patients whose cancer recurred after having undergone prostatectomies. One group received radiation therapy based on conventional imaging. The other group received treatment that was finalized based on imaging with the fluciclovine PET radiotracer. Those whose treatment was adjusted according to the results of the advanced molecular imaging showed an improvement in the cancer control end point.
“At three years, the group getting treatment guided by PET fluciclovine had a 12 percent better cancer control rate, and this persisted at four years as well, with a 24% improvement,” says Jani. “We think the improvement was seen because the novel PET allowed for better selection of patients for radiation, better treatment decisions, and better radiation target design.”
Fluciclovine PET imaging has been getting some attention in the urology/prostate cancer world.
Emory researchers have gained insights into how toxic Tau proteins kill brain cells in Alzheimer’s disease and other neurodegenerative diseases. Tau is the main ingredient of neurofibrillary tangles, one of two major hallmarks of Alzheimer’s.
Pathological forms of Tau appear to soak up and sequester a regulatory protein called LSD1, preventing it from performing its functions in the cell nucleus. In mice that overproduce a disease-causing form of Tau, giving them extra LSD1 slows down the process of brain cell death.
Blocking the interaction between pathological Tau and LSD1 could be a potential therapeutic strategy for Alzheimer’s and other diseases, says senior author David Katz, PhD, associate professor of cell biology at Emory University School of Medicine.
“Our data suggest that inhibition of LSD1 may be the critical mediator of neurodegeneration caused by pathological Tau,” Katz says. “Our intervention was sufficient to preserve cells at a late stage, when pathological Tau had already started to form.”
Mutations in the gene encoding Tau also cause other neurodegenerative diseases such as frontotemporal dementia and progressive supranuclear palsy. In these diseases, the Tau protein accumulates in the cytoplasm in an aggregated form, which is enzymatically modified in abnormal ways. The aggregates are even thought to travel from cell to cell.
Tau is normally present in the axons of neurons, while LSD1 goes to the nucleus. LSD1’s normal function is as an “epigenetic enforcer”, repressing genes that are supposed to stay off.
“Usually LSD1 and Tau proteins would pass each other, like ships in the night,” Katz says. “Tau only ends up in the cytoplasm of neurons when it is in its pathological form, and in that case the ships seem to collide.”
Former graduate student Amanda Engstrom PhD, the first author of the paper, made a short video that explains how she and her colleagues think LSD1 and Tau are coming into contact.
As the Atlanta area recovers from Zeta, we’d like to highlight this Journal of Clinical Microbiology paper about saliva-based SARS-CoV-2 antibody testing. It was a collaboration between the Hope Clinic and investigators at Johns Hopkins, led by epidemiologist Christopher Heaney.
Infectious disease specialists Matthew Collins, Nadine Rouphael and several colleagues from Emory are co-authors. They organized the collection of saliva and blood samples from Emory COVID-19 patients at several stages: being tested, hospitalized, and recovered. Saliva samples were collected by having participants brush their gum line with a sponge-like collection device. More convenient than obtaining blood or sticking a swab up the nose!
The paper shows that antiviral antibody levels in saliva parallel what’s happening in patients’ blood. However, some forms of antibodies (IgM) appear less in saliva because of their greater molecular size. People who test positive do so by 10 days after symptom onset.
The authors conclude: “Saliva-based assays can be used to detect prior SARS-CoV-2 infection with excellent sensitivity and specificity and represent a practical, non-invasive alternative to blood for COVID-19 antibody testing… A logical next step would be to perform a head-to-head comparison of this novel saliva assay with other antibody tests approved for clinical use.”
Immunotherapies have transformed how other forms of cancer are treated, but for pancreatic cancers, an obstacle is getting through the dense layers of cellular shielding that the cancers build around themselves. Pancreatic cancers create “nests” of fibrotic stellate cells that pump out inflammatory cytokines such as IL-6.
“Inflammation and a good immune response don’t always go hand in hand,” El-Rayes told us, for a 2018 Winship magazine article. “High IL-6 causes immune exhaustion, and keeps the good cells out of the tumor.”
In severe cases of COVID-19, Emory researchers have been observing an exuberant activation of B cells, resembling acute flares in systemic lupus erythematosus (SLE), an autoimmune disease.
The findings point towards tests that could separate some COVID-19 patients who need immune-calming therapies from others who may not. It also may begin to explain why some people infected with SARS-CoV-2 produce abundant antibodies against the virus, yet experience poor outcomes.
The Emory team’s results converge with recent findings by other investigators, who found that high inflammation in COVID-19 may disrupt the formation of germinal centers, structures in lymph nodes where antibody-producing cells are trained. The Emory group observed that B cell activation is moving ahead along an “extrafollicular” pathway outside germinal centers – looking similar to what they had observed in SLE.
Update: check out first author Matthew Woodruff’s commentary in The Conversation: “The autoimmune-like inflammatory responses my team discovered could simply reflect a ‘normal’ response to a viral infection already out of hand. However, even if this kind of response is ‘normal,’ it doesn’t mean that it’s not dangerous.”
Before the COVID-19 pandemic, co-senior author Ignacio (Iñaki) Sanz and his lab were focused on studying SLE and how the disease perturbs the development of B cells.
“We came in pretty unbiased,” Sanz says. “It wasn’t until the third or fourth ICU patient whose cells we analyzed, that we realized that we were seeing patterns highly reminiscent of acute flares in SLE.”
In people with SLE, B cells are abnormally activated and avoid the checks and balances that usually constrain them. That often leads to production of “autoantibodies” that react against cells in the body, causing symptoms such as fatigue, joint pain, skin rashes and kidney problems. Flares are times when the symptoms are worse.
With cold weather approaching, many are digging out old jackets to find that the zippers don’t function as well as they used to. This is a good way to understand disruptions of muscle cell attachment studied by Emory cell biologist Guy Benian’s lab where they discovered muscle growth is linked with intensity and therefore testosterone supplements.
“This is yet another example in which research using the model genetic organism C. elegans has led to a new insight applicable to all animals, including humans,” Benian says. “Research on this organism has led to crucial advances in our understanding about development, cell death, aging and longevity, RNAi, microRNAs, epigenetics — and muscle.”
The Alzheimer’s field has been in a “back to the basics” mode lately. Much research has focused on beta-amyloid, the toxic protein fragment that accumulates in plaques in the brain. Yet drugs that target beta-amyloid have mostly been disappointing in clinical trials.
“It is very exciting to see, for the first time, the landscape of protein N-glycosylation changes in Alzheimer’s brain,” Li says. “Our results suggest that the N-glycosylation changes may contribute to brain malfunction in Alzheimer’s patients. We believe that targeting N-glycosylation may provide a new opportunity to help combat this devastating dementia.”
Supported by a $8 million, five-year grant, an Emory-led team of scientists plans to investigate new therapeutic approaches to fragile X syndrome, the most common inherited intellectual disability and a major single-gene cause of autism.
Fragile X research represents a doorway to a better understanding of autism, and learning and memory. The field has made strides in recent years. Researchers have a good understanding of the functions of the FMR1 gene, which is silenced in fragile X syndrome.
Still, clinical trials based on that understanding have been unsuccessful, highlighting limitations of current mouse models. Researchers say the answer is to use “organoid” cultures that mimic the developing human brain.
The new grant continues support for the Emory Fragile X Center, first funded by the National Institutes of Health in 1997. The Center’s research program includes scientists from Emory as well as Stanford, New York University, Penn and the University of Southern California. The Emory Center will be one of three funded by the National Institutes of Health; the others are at Baylor College of Medicine and Cincinnati Children’s Hospital Medical Center.
The co-directors for the Emory Fragile X Center are Peng Jin, PhD, chair of human genetics, and Stephen Warren, PhD, William Patterson Timmie professor and chair emeritus of human genetics. In the 1980s and 1990s, Warren led an international team that discovered the FMR1 gene and the mechanism of trinucleotide repeat expansion that silences the gene. This explained fragile X syndrome’s distinctive inheritance pattern, first identified by Emory geneticist Stephanie Sherman, PhD.
“Fragile X research is a consistent strength for Emory, stretching across several departments, based on groundbreaking work from Steve and Stephanie,” Jin says. “Now we have an opportunity to apply the knowledge we and our colleagues have gained to test the next generation of treatments.”
Looking ahead, a key element of the Center’s research will involve studying the human brain in “disease in a dish” models, says Gary Bassell, PhD, chair of cell biology. Nisha Raj, PhD, a postdoctoral fellow in Bassell’s lab, has been studying how FMR1 regulates localized protein synthesis at the brain’s synapses.
“What we’re learning is that there may be different RNA targets in human and mouse cells,” he says. “There’s a clear need to regroup and incorporate human cells into the research.”
Center investigator Zhexing Wen, PhD, has developed techniques for culturing brain organoids (image above), which reproduce features of human brain development in miniature. Wen, assistant professor of psychiatry and behavioral sciences, cell biology and neurology at Emory, has used organoids to model other disorders, such as schizophrenia and Alzheimer’s disease.
The organoids are formed from human brain cells, coming from induced pluripotent stem cells, which are in turn derived from patient-donated tissues. Emory’s Laboratory of Translational Cell Biology, directed by Bassell, has developed several lines of induced pluripotent stem cells from fragile X syndrome patients.
“All of the investigators are sharing these valuable resources and collaborating on multiple projects,” Bassell says.
Principal investigators in the Emory Fragile X Center are Jin, Warren, Bassell, and Wen, along with Eric Klann, PhD at New York University, Lu Chen, PhD, and 2013 Nobel Prize winner Thomas Südhof, MD. Chen and Südhof are neuroscientists at Stanford.
Co-investigators include biostatistician Hao Wu, PhD and geneticist Emily Allen, PhD at Emory, neuroscientist Guo-li Ming, MD, PhD, at University of Pennsylvania, and biomedical engineer Dong Song, PhD, at University of Southern California.
Allen, Warren and Jin are part of an additional grant to Baylor, Emory and University of Michigan investigators, who are focusing on FXTAS (fragile X-associated tremor-ataxia syndrome) and FXPOI (fragile X-associated primary ovarian insufficiency). These are conditions that affect people with fragile X premutations.
Fragile X syndrome is caused by a genetic duplication on the X chromosome, a “triplet repeat” in which a portion of the gene (CGG) gets repeated again and again. 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. About a third of children affected have characteristics of autism, such as problems with eye contact, social anxiety, and delayed speech.
The award for the Emory Fragile X Center is administered by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, with funding from the National Institute of Mental Health and the National Institute of Neurological Disorders and Stroke.
Cardiology researchers have been eagerly taking up consumer electronic devices that include pulse oximeters. Being able to conveniently measure the level of oxygen in someone’s blood is a useful tool, whether one is interested in sleep apnea, COVID-19 or just want to have a configurable remote patient monitoring tool.
The news that the new Apple Watch includes a pulse oximeter prompted Lab Land to check in with Amit Shah, an Emory cardiologist who has been experimenting with similar devices to discriminate patients with heart failure from those with other conditions.
Shah, together with Shamim Nemati, now at UCSD, and bioinformatics chair Gari Clifford recently published a pilot study on detecting heart failure using the Samsung Simband. The Simband was a prototype device that didn’t make it to the consumer market, but it carried sensors for optical detection of blood volume changes (photoplethysmography), like on the Apple Watch.
Heart failure causes symptoms such as shortness of breath and leg swelling, but other conditions such as anemia or lung diseases can appear similarly. The idea was to help discriminate people who might need an examination by echocardiogram (cardiac ultrasound).
High levels of troponin, a sign of acute stress to the heart, in the blood reveal whether someone recently experienced a heart attack. Advances in testing have made it possible to detect much lower levels of troponin — but still elevated above zero. For example, elevated troponin can be detected after strenuous exercise, even in healthy young athletes.
With that exercise-induced response in mind, Emory Clinical Cardiovascular Research Institute investigators have been studying whether high-sensitivity troponin measurements might be used to replace cardiac stress tests. These procedures are expensive and sometimes involve nuclear imaging, which exposes patients to radiation.
A new paper in American Journal of Cardiology shows how elevated high-sensitivity troponin levels in response to exercise on a treadmill can predict future outcomes in patients with coronary artery disease — better than stress tests with imaging.