Microbiome critical for bone hormone action

PTH (parathyroid hormone) increases calcium levels in the blood and can either drive bone loss or bone formation, depending on how it is produced or Read more

More NMDA but less excitotoxicity? Now possible

Many researchers have wanted to enhance NMDA receptor signals to treat disorders such as schizophrenia. But at the same time, they need to avoid killing neurons with “excitotoxicity”, which comes from excess calcium entering the Read more

Update on pancreatic cancer: images and clinical trial

In 2018, Winship magazine had a feature story on pancreatic cancer. Our team developed an illustration that we hoped could convey the tumors’ complex structure, which contributes to making them difficult to treat. Oncologist Bassel El-Rayes described how the tumors recruit other cells to form a protective shell. "If you look at a tumor from the pancreas, you will see small nests of cells embedded in scar tissue," he says. "The cancer uses this scar Read more

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A new frame of reference — on ribosome frameshifting

It’s a fundamental rule governing how the genetic code works. Ribosomes, the factories that assemble proteins in all types of living cells, read three letters (or nucleotides) of messenger RNA at a time.

In some instances, the ribosome can bend its rules, and read either two or four nucleotides, altering how downstream information is read. Biologists call this normally rare event ribosomal frameshifting. For an ordinary gene, the event of a frameshift turns the rest of the ensuing protein into nonsense. However, many viruses exploit frameshifting, because they can then have overlapping genes and fit more information into a limited space.

Regulated frameshifting takes place in human genes too, and understanding frameshifting is key to recent efforts to expand the genetic code. Researchers are aiming to use the process to customize proteins for industrial and pharmaceutical applications, by inserting amino acid building blocks not found in nature.

“Going back to the 1960s, when the genetic code was first revealed, there were many studies on ribosomal frameshifting, yet no-one really knows how it works on a molecular and mechanistic level,” says Christine Dunham, PhD, assistant professor of biochemistry at Emory University School of Medicine. “What we do know is that the ‘yardstick’ model that appears in a lot of textbooks, saying that the anticodon loop dictates the number of nucleotides decoded, while elegant, is probably incorrect.”

Dunham, who first studied the topic as a postdoc, and her colleagues published a paper this week in PNAS where they outline a model for how ribosomal frameshifting occurs, based on structural studies of the ribosome interacting with some of its helper machinery. Co-first authors of the paper are postdoctoral fellows Tatsuya Maehigashi, PhD and Jack Dunkle, PhD.

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Antibiotic resistance enzyme caught in the act

Resistance to an entire class of antibiotics – aminoglycosides — has the potential to spread to many types of bacteria, according to new biochemistry research.

A mobile gene called NpmA was discovered in E. coli bacteria isolated from a Japanese patient several years ago. Global spread of NpmA and related antibiotic resistance enzymes could disable an entire class of tools doctors use to fight serious or life-threatening infections.

Using X-ray crystallography, researchers at Emory made an atomic-scale snapshot of how the enzyme encoded by NpmA interacts with part of the ribosome, protein factories essential for all cells to function. NpmA imparts a tiny chemical change that makes the ribosome, and the bacteria, resistant to the drugs’ effects.

The results, published in PNAS, provide clues to the threat NpmA poses, but also reveal potential targets to develop drugs that could overcome resistance from this group of enzymes.

First author of the paper is postdoctoral fellow Jack Dunkle, PhD. Co-senior authors are assistant professor of biochemistry Christine Dunham, PhD and associate professor of biochemistry Graeme Conn, PhD. Read more

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Buzzword overuse alert: epigenetics

The term “epigenetics” has come up a lot here on the Lab Land blog.

In June a discussion came up on Twitter about scientific terms that are overused. I began to wonder whether I was contributing to the problem and may need to tighten up my use of the word “epigenetics.” Read more

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Flashback to LSD research from the 1950s

Accompanying 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

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Hunting for potential diabetes drugs

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.

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CRISPR gene editing can miss its mark

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.

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Charlotte Observer highlights Lab Land

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

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A CRISPR way to edit DNA

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.”

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.

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C. difficile: its name says what it is

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.

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Trend: epigenomics

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

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