‘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 Read more
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. Read more
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 Read moreAccompanying Kai Kupferschmidt’s July 3 feature in Science, which discusses a current revival of clinical research on hallucinogens such as LSD and psilocybin, was a curious historical photo. The 1955 copyrighted photo depicts pharmacologist Harry Williams squirting LSD into the mouth of Carl Pfeiffer, chair of pharmacology at Emory during the 1950’s. Read more
Pathologist Keqiang Ye and his colleagues have been prolific in finding small molecules able to mimic the action of the brain growth factor BDNF. Aiming to export that success to similar molecules (that is, other receptor tyrosine kinases), they have been searching for potential drugs able to substitute for insulin.
Diabetes drugs Januvia (sitagliptin) and Lantus (insulin analog) are top 20 drugs, both in terms of dollars and monthly prescriptions, and the inconvenience of insulin injection is well known, so the business potential is clear.
A paper published in the journal Diabetes in April describes Ye’s team’s identification of a compound called chaetochromin A, which was originally isolated by Japanese researchers studying toxins found in moldy rice. Chaetochromin A can drive down blood sugar in normal, type 1 diabetes and type 2 diabetes mouse models, the authors show.
See here for another compound identified in Ye’s lab with similar properties.
Yanni Lin, TJ Cradick, Gang Bao and colleagues from Georgia Tech and Emory reported recently in Nucleic Acids Research on how the CRISPR/Cas9 gene editing system can sometimes miss its mark.
CRISPR/Cas9 has received abundant coverage from science-focused media outlets. Basically, it is a convenient system for cutting DNA in cells in a precise way. This paper shows that the CRISPR/Cas9 system can sometimes cut DNA in places that don’t exactly match the designed target.
Here we show that CRISPR/Cas9 systems can have off-target cleavage when DNA sequences have an extra base or a missing base at various locations compared with the corresponding RNA guide strand…Our results suggest the need to perform comprehensive off-target analysis by considering cleavage due to DNA and sgRNA bulges in addition to base mismatches.
CRISPR/Cas9 could be used to develop therapies for humans for genetic blood diseases such as sickle cell or thalassemia, and this paper does not change that potential. But the authors are cautioning fellow scientists that they need to design their tools carefully and perform quality control. Other investigators have made similar findings.
Thanks to Amber Veverka for featuring Lab Land as part of the Charlotte Observer’s regular look at science-oriented blogs. I reproduce my responses here to add some links.
Describe the range of health science research you are covering on Lab Land – and a little bit about your intended audience.
Any intriguing idea emerging from basic or clinical biomedical research happening at Emory. The blog is aimed at people who are somewhat familiar with biological concepts, like graduate students, postdocs or science journalists.
What are some of the most exciting advances you’ve recently written about?
Here are a few!
*Neuroscientists found that a mouse can pass on a learned sensitivity to a smell to its offspring
*Cardiologists discovered that heart muscle cells in mice grow in a dramatic spurt after birth, with implications for the treatment of congenital heart defects.
*Some peoples’ brains produce something that acts like a sleeping pill, giving them hypersomnia. It’s not clear what this mysterious brain chemical is yet.
*Less invasive epilepsy surgery involving lasers; seizure control with fewer cognitive side effects
*Biomedical engineers are developing ways to prevent stem cells from being washed out of the heart Read more
The CRISPR/Cas gene editing system has a lot of buzz behind it: an amusingly crunchy name, an intriguing origin, and potential uses both in research labs and even in the clinic. We heard that Emory scientists are testing it, so an explainer was in order.
The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) system was originally discovered by dairy industry researchers seeking to prevent phages, the viruses that infect bacteria, from ruining the cultures used to make cheese and yogurt. Bacteria incorporate small bits of DNA from phages into their CRISPR region and use that information to fight off the phages by chewing up their DNA.
At Emory, infectious disease specialist David Weiss has published research on CRISPR in some types of pathogenic bacteria, showing that they need parts of the CRISPR system to evade their hosts and stay infectious. Biologist Bruce Levin has modeled CRISPR-mediated immunity’s role in bacterial evolution.
What has attracted considerable attention recently is CRISPR/Cas-derived technology, which offers the ability to dive into the genome and make a very precise change. Scientists have figured out how to retool the CRISPR/Cas machinery – the enzymes that do the chewing of the phage DNA — into enzymes that can be targeted by an external guide.
For biologists in the laboratory, this is a way to probe a gene’s function by making an animal with its genes altered in a certain way. The method is gaining popularity here at Emory. Geneticist Peng Jin reports:
“CRISPR is much more efficient and quicker than traditional homologous recombination. One can directly inject the plasmid and guide RNA into mouse embryo to make knockout mice. You can also target multiple genes at the same time.â€
The traditional method Jin refers to involves taking cultured embryonic stem cells, zapping DNA carrying a modified or disabled gene into them, and hoping that the cells’ repair machinery sews the DNA into the genome in the right way. Usually they have to use antibiotics and drugs to screen out all the cells where the DNA gets jammed into the genome haphazardly. Also, Jin adds that CRISPR/Cas technology can be used for whole-genome screens.
Tamara Caspary, a developmental biologist and scientific director of Emory’s transgenic mouse and gene targeting core, says she and her core team are in the process of developing and validating CRISPR, so that the technique could be accessible to many Emory investigators.
Potential clinical uses: Japanese scientists have proposed that CRISPR/Cas be employed against HIV infection. One can envision similar gene therapy applications.
If you’re looking for an expert on the “notorious†bacterium Clostridium difficile, consider Emory microbiologist Shonna McBride.
C. difficile is a prominent threat to public health, causing potential fatal cases of diarrheal disease. C. difficile can take over in someone’s intestines after antibiotics clear away other bacteria, making it dangerous for vulnerable patients in health care facilities. Healthcare-associated infections caused by other types of bacteria such as MRSA have been declining, leaving C. difficile as the most common cause, according to recently released data from the CDC.
Shonna McBride, PhD
McBride’s work focuses on how C. difficile is able to resist antimicrobial peptides produced by our bodies that keep other varieties of bacteria in check.
A 2013 paper from her lab defines genes that control C. difficile’s process for sequestering these peptides. It appears that its ability to resist host antimicrobial peptides evolved out of a system for resisting weapons other bacteria use against each other.
Since C. difficile requires an oxygen-free environment to grow, studying it can be more difficult than other bacteria. The McBride lab has a recent “video article†in the Journal of Visualized Experiments explaining how to do so using specialized equipment.
McBride explains in a recent Microbe magazine cover article that C. difficile’s ability to form spores is connected to the threat it poses:
Without the ability to form spores, the strict anaerobe C. diffıcile would quickly die in the presence of atmospheric oxygen. However, the intrinsic resilience of these spores makes them diffıcult to eradicate, facilitating the spread of this pathogen to new hosts, particularly in health care settings where they withstand many of the most potent disinfectants.
Yet the process of sporulation is markedly different in C. difficile compared with other kinds of bacteria, she says in the review.
Nature News recently described a trend noticeable at Emory and elsewhere. That trend is epigenomics: studying the patterns of chemical groups that adorn DNA sequences and influence their activity. Often this means taking a comprehensive genome-wide look at the patterns of DNA methylation.
DNA methylation is a chemical modification analogous to punctuation or a highlighter or censor’s pen. It doesn’t change the letters of the DNA but it does change how that information is received.
One recent example of epigenomics from Emory is a collaboration between psychiatrist Andrew Miller and oncologist Mylin Torres, examining the long-lasting marks left by chemotherapy in the blood cells of breast cancer patients.
Their co-author Alicia Smith, who specializes in the intersection of psychiatry and genetics, reports “EWAS or epigenome-wise association studies are being used in complex disease research to suggest genes that may be involved in etiology or symptoms. They’re used in medication or diet studies to demonstrate efficacy or suggest side effects.  They’re also used in longitudinal studies to see if particular exposures or characteristics (i.e. low birthweight) have long-term consequences.” Read more
Emory Genetics Laboratory, with its whole exome sequencing business accelerating, is launching a new Medical EmExome product to provide clinicians with additional confidence and coverage. To go with this, EGL director Madhuri Hegde sent us some examples of recent diagnostic successes.
One of these was part of a paper that was recently published in the journal Genetics in Medicine: a young girl with multiple symptoms (developmental delay, movement disorder, digestive and breathing problems) was diagnosed with a new type of metabolic disorder, having inherited two mutated copies of the NGLY1 gene.
Two parents whose children were diagnosed with NGLY1 mutations have an interesting commentary in the same journal, describing how next-generation sequencing and social media went hand-in-hand. [this story was also on CNN.com as “Kids who don’t cry”] Here is an excerpt from the parents’ essay:
Six of the eight patients presented in the accompanying article were linked together after parents, physicians, or scientists working on isolated cases searched online for “NGLY1.†They found a blog post describing the disorder written by the parents of the first confirmed patient. The blog chronicles the boy’s journey (initial evaluation, visits to multiple specialists, incorrect diagnoses, and ultimately the discovery of heterozygous mutations in NGLY1). It was this personal account that allowed the ordering physician, who had been tracking a second patient with NGLY1 variants, to feel confident that the two patients were suffering from the same disorder. Another patient was discovered, on a distant continent, when a parent’s Internet search for his/her child’s symptoms stumbled upon the aforementioned blog. This prompted the parents to suggest targeted NGLY1 sequencing to their child’s physician. Parent/patient-to-physician collaboration such as this is remarkable and is likely happening in other rare diseases with the advent of NGS.
As untrained people, we are not qualified to analyze whole-exome/whole-genome data. We cannot develop a therapeutic compound. We cannot design a diagnostic assay. That being said, parents can offer observations and ideas, and we can push for solutions. Nineteen months after the initial report by Need et al., five viable approaches to treatment are under active consideration, thanks to relentless digging by afflicted families…
Another case study Hegde sent us describes a baby that was born but died after just 10 days, unable to swallow and with poor muscle tone. During pregnancy, the mother had felt reduced fetal movement. For the baby, doctors ordered a variety of gene panels without finding abnormalities, but a muscle biopsy detected signs of congenital muscular dystrophy, type unknown. Whole exome sequencing was able to show that the baby’s disease came from inheriting two mutated forms of the RYR1 gene. Now the mother is pregnant again, and reports feeling lots of movement.
A molecular signature seen in blood from patients who are experiencing an acute heart attack may also predict the risk of cardiovascular death over the next few years, Emory researchers have found.
The results were presented Monday at the American College of Cardiology meeting in Washington DC by cardiovascular research fellow Nima Ghasemzadeh, MD. Ghasemzadeh is working with Arshed Quyyumi, MD, director of Emory’s Clinical Cardiovascular Research Center, as well as Greg Gibson, PhD, director of the Integrative Genomics Center at Georgia Tech.
Ghasemzadeh and colleagues examined 337 patients undergoing cardiac catheterization at Emory. Just 18 percent of the patients in this group were having a heart attack. This research is a reminder that the majority of patients who undergo cardiac catheterization, and thus are suspected of experiencing a heart attack, are not actually having one at that moment. Read more
The 1966 movie “Fantastic Voyage†presented a vision of the future that includes tiny machines gliding through the body and repairing injuries. Almost 50 years later, scientists are figuring out how to form building blocks for such machines from DNA.
A new paper in Science describes DNA-based polyhedral shapes that are larger and stronger than scientists have built before. Right now, these are just static shapes. But they provide the scaffolding on which scientists could build robot walkers, or cages with doors that open and close. Already, researchers are talking about how such structures could be used to deliver drugs precisely to particular cells or locations in the body.
“Currently DNA self-assembly is perhaps one of the most promising methods for making those nanoscale machines,†says co-author Yonggang Ke, PhD, who recently joined the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University as assistant professor.
The research team was led by Peng Yin, PhD at Harvard’s Wyss Institute for Biologically Inspired Engineering. Working with the same team, Ke was also first author on a 2012 paper in Science describing “DNA bricks†resembling LEGO® blocks.
In the current paper, the shapes are made up of strut-reinforced tripods, which assemble themselves from individual DNA strands in a process called “DNA origami.†Already, at 5 megadaltons, each tripod is more massive than the largest known single protein (titin, involved in muscle contraction) and more massive than a ribosome, one of the cellular factories in which proteins are made. The tripods in turn can form prism-like structures, 100 nanometers on each side, that begin to approach the size of cellular organelles such as mitochondria.
The prism structures are still too small to see with light microscopes. Because electron microscopy requires objects to be dried and flattened, the researchers used a fluorescence-based imaging technique called “DNA PAINT†to visualize the jungle-gym-like structures in solution.
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DNA is not necessarily the most durable material for building a tiny machine. It is vulnerable to chemical attack, and enzymes inside the body readily chew up DNA, especially exposed ends. However, DNA presents some advantages: it’s easy (and cheap) to synthesize in the laboratory, and DNA base-pairing is selective. In fact, says Ke, these intricate structures assemble themselves: put all the components together in one tube, and all the DNA sequences that are supposed to pair up find each other.
Each leg of the tripod is made of 16 DNA double helices, connected together in ways that constrain the structure and make it stiff. The tripods have “sticky ends†that are selective and can assemble into the larger pyramids or prism structures. Previous efforts to build polyhedral structures were like trying to make a jungle gym out of rope: they were too floppy and hard to assemble.
To see the pyramid and prism structures, the research team used the “DNA-PAINT†technique, which uses fluorescent DNA probes that transiently bind to the DNA structures. This method enables visualization of structures that cannot be seen with a conventional light microscope. Why not simply make the DNA structures themselves fluorescent? Because shining strong light on such structures would quickly quench their fluorescence signal.
In his own work in Atlanta, Ke says he plans to further customize the DNA structures, combining the DNA with additional chemistry to add other functional molecules, including proteins or nanoparticles. He is especially interested in developing DNA-based materials that can manipulate or respond to light or carry magnets, with potential biomedical applications such as MRI imaging or targeted drug delivery.