Quinn Eastman

Probing a puzzling form of muscular dystrophy

Two researchers at Emory, Anita Corbett and Grace Pavlath, recently have combined their expertise to probe how a puzzling form of muscular dystrophy develops.

Oculopharyngeal muscular dystrophy (OPMD) is an inherited type of muscular dystrophy that primarily affects muscles of the face and throat. In the video below, Anita Corbett explains how this affects patients as they get older.


The mutations that cause the disease make a protein called PABPN1 longer and stickier than normal, and the mutated protein appears to form clumps in muscle cells.

The puzzle lies in that PABPN1 (poly A binding protein nuclear 1) can be found everywhere in the body, but it’s not clear why the mutated protein specifically affects muscle cells — or why the muscles in the face and throat are especially vulnerable.

In December 2009, Corbett, Pavlath and postdoctoral fellow Luciano Apponi published a paper where they suggest that the clumps of mutated protein, which some researchers have proposed to be toxic, might not be the whole story. A lack of functioning PABPN1 might be just as strong a factor in the disease, they’ve discovered.

The results will appear in a future issue of the journal Human Molecular Genetics.

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Nanotechnology may help surgeons detect cancer

What a cancer patient wants to know after surgery can be expressed succinctly: “Did you get everything?” Having a confident answer to that question can be difficult, because when they originate or metastasize, tumors are microscopic.

Considerable advances have been made in “targeted therapy” for cancer, but the wealth of information available on the molecular characteristics of cancer cells hasn’t given doctors good tools for detecting cancer during surgery – yet.

Even the much-heralded advent of robotic surgery has not led to clear benefits for prostate cancer patients in the area of long-term cancer control, a recent New York Times article reports.

At Emory and Georgia Tech’s joint department for biomedical engineering, Shuming Nie and his colleagues are developing tools that could help surgeons define tumor margins in human patients.

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A new class of brain-protecting drugs

Pathologist Keqiang Ye has made a series of discoveries recently, arising from his investigations of substances that can mimic the growth factor BDNF (brain-derived neurotrophic factor).

BDNF is a protein produced by the brain that pushes neurons to withstand stress and make new connections. Some neuroscientists have described BDNF as “Miracle Gro for brain cells.”

“BDNF has been studied extensively for its ability to protect neurons vulnerable to degeneration in several diseases, such as ALS, Parkinson’s and Alzheimer’s disease,” Ye says. “The trouble with BDNF is one of delivery. It’s a protein, so it can’t cross the blood-brain barrier and degrades quickly.”

Working with Ye, postdoctoral fellow Sung-Wuk Jang identified a compound called 7,8-dihydroxyflavone that can duplicate BDNF’s effects on neurons and can protect them against damage in animal models of seizure, stroke and Parkinson’s disease. The compound’s selective effects suggest that it could be the founder of a new class of brain-protecting drugs. The results were published in Proceedings of the National Academy of Sciences.

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Peripheral artery disease: can help come from the bone marrow?

Peripheral artery disease affects millions of people in the United States. It’s basically hardening of the arteries (atherosclerosis) leading to problems with getting enough blood to the limbs. Symptoms of severe PAD include leg pain that doesn’t go away once exertion stops and wounds that heal slowly or not at all.

Lifestyle changes, medication and surgery can address some cases of PAD, but often the disease is not recognized until it has advanced considerably. At Emory, cardiologist Arshed Quyyumi has been exploring whether a patient’s own bone marrow cells can repair the arteries in his or her limbs.

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Creating tools for next-generation sequencing

Emory biochemist Eric Ortlund participated in a study that was recently published in Proceedings of the National Academy of Sciences, which involves tinkering with billions of years of evolution by introducing mutations into DNA polymerase.

What may soon be old-fashioned: next-generation sequencing combines many reactions like the one depicted above into one pot

DNA polymerases, enzymes that replicate and repair DNA, assemble individual letters in the genetic code on a template. The PNAS paper describes efforts to modify Taq DNA polymerase to get it to accept “reversible terminators.” (Taq = Thermus aquaticus, a variety of bacteria that lives in hot springs and thus has heat-resistant enzymes, a useful property for DNA sequencing)

Ortlund was involved because he specializes in looking at how evolution shapes protein structure. Along with co-author Eric Gaucher, Ortlund is part of the Fundamental and Applied Molecular Evolution Center at Emory and the Georgia Institute of Technology.

To sequence DNA faster and more cheaply, scientists are trying to get DNA polymerases to accept new building blocks. This could facilitate next-generation sequencing technology that uses “reversible terminators” to sequence many DNA templates in parallel.

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The importance of upbringing

Every time scientists identify genetic risk factors for a human disease or a personality trait, it seems like more weight accumulates on the “nature” side of the grand balance between nature and nurture.

That’s why it’s important to remember how much prenatal and childhood experiences such as education, nutrition, environmental exposures and stress influence later development.

At the Emory/Georgia Tech Predictive Health Symposium in December, biologist Victor Corces outlined this concept using a particularly evocative example: bees. A queen bee and a worker bee share the same DNA, so the only thing that determines whether an insect will become the next queen is whether she consumes royal jelly.

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Personal genomics: out of the bottle

Do you really want to know? That’s the question more and more people will be faced with, as personal genetic testing becomes more widespread.

Andrew Faucett discussed some of the emerging issues in “personal genomics” that will confront both doctors and patients at Emory’s Predictive Health Symposium in December. Faucett is an expert in the field of genetic testing and genetic counseling and an assistant professor in Emory’s Department of Human Genetics.

For example, does a man want to find out whether he is really the father of a baby? A recent New York Times magazine article explores this issue.

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Questions only a network of pathologists can answer

When a patient is fighting a brain tumor, pathologists usually obtain a tiny bit of the tumor, either through a biopsy or after surgery, and prepare a microscope slide. Looking at the slide, they can sometimes (but not always) tell what type of tumor it is. That allows them to have an answer, however tentative, for that critical question from the patient: “How long have do I have?” as well as give guidance on what kind of treatment will be best.

Dan Brat, a pathologist specializing in brain tumors at Emory Winship Cancer Institute, gave a presentation this week explaining how he has been asking more complicated questions, ones only a network of pathologists armed with sophisticated computers can answer:

  • What genes tend to be turned on or off in the various types of brain tumors?
  • What does the pattern look like when a tumor is running out of oxygen?
  • What if we get a “robot pathologist” to look at hundreds of thousands of brain tumor slides?
Under the microscope, the shapes of cell nuclei in brain tumors look different depending on the type of tumor.

Under the microscope, the shapes of cell nuclei in brain tumors look different depending on the type of tumor.

Brat was speaking at a caBIG (cancer Biomedical Informatics Grid) conference, taking place at the Emory Conference Center this week. caBIG is a computer network sponsored by the National Cancer Institute that allows doctors to share experimental data on cancers. Brat explained that low-grade brain tumors come in two varieties: oligodendrogliomas and astrocytomas. Under the microscope, cell nuclei in the first tend to look round and smooth, but the second look elongated and rough. Kind of like the differences between an orange and a potato, he said.  He and colleague Jun Kong designed a computer program that could tell one from the other. They had the program look through almost 400,000 slides, using resources compiled through caBIG (Rembrandt and Cancer Genome Atlas databases). Sifting through the data, they could find that certain genes are turned on in each kind of tumor.

Imagine a "robot pathologist" that can sift through thousands of images from brain tumor samples.

Imagine a "robot pathologist" that can sift through thousands of images from brain tumor samples.

Daniel Brat, MD, PhD, principal investigator for the In Silico Brain Tumor Research Center

Daniel Brat, MD, PhD, principal investigator for the In Silico Brain Tumor Research Center

Eventually, this kind of information could help a patient with a brain tumor get good responses to those “How long?” and “How am I going to get through this?” questions.

Joel Saltz, who leads Emory’s Center for Comprehensive Informatics, has been a central figure in developing tools for centers such as Emory’s In Silico Brain Tumor Research Center. In September 2009, Emory was selected to host one of five “In Silico Research Centers of Excellence” by the National Cancer Institute.

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How muscles get stronger — and the nose knows

Scientists at Emory studying muscle repair have discovered an unexpected function for odorant receptors.

Odorant receptors’ best known functions take place inside the nose. By sending signals when they encounter substances wafting through the air, odorant receptors let us know what we’re smelling. Working with pharmacologist Grace Pavlath, graduate student Christine Griffin found that the gene for one particular odorant receptor is turned on in muscle cells during muscle repair.

The activation of the odorant receptor gene MOR23 is visible in muscle tissue in pink. Cell nuclei appear as blue.

The activation of the odorant receptor gene MOR23 is visible in muscle tissue in pink. Cell nuclei appear as blue.

Grace Pavlath, PhD

Grace Pavlath, PhD

Christine Griffin

Christine Griffin

“Normally MOR23 is not turned on when the tissue is at rest, so we wouldn’t have picked it up without looking specifically at muscle injury,” Pavlath says. “There is no way we would have guessed this.”

The finding could lead to new ways to treat muscular dystrophies and muscle wasting diseases, and also suggests that odorant receptors may have additional unexpected functions in other tissues.

While we’re on the topic of odorant receptors, a great article in November’s Howard Hughes Medical Institute Bulletin describes Emory psychiatrist Kerry Ressler’s work with Linda Buck when he was a graduate student.

From the article:

“I had never thought about smell a day in my life until I heard Linda give her talk,” Ressler says, still jazzed by the memory, “and I was absolutely blown away.” Buck had methodically identified about 1,000 odorant receptor (OR) genes and she outlined an orderly plan for decoding their function.

…Over the next three years, Ressler’s dissertation work contributed to the accomplishments that earned Buck the 2004 Nobel Prize in Physiology or Medicine, which she shared with HHMI investigator Richard Axel. Prominently displayed in Ressler’s Emory office is a framed picture of him with Buck at the Stockholm ceremony, both grinning broadly in formalwear.”

Ressler and his colleagues at Yerkes National Primate Research Center now study how fearsome memories become lodged in our brains. Since smell is often described as accessing the most primitive parts of the brain, the connection between Ressler’s past and present makes sense.

Kerry Ressler, MD, PhD, when he's not in Stockholm

Kerry Ressler, MD, PhD, when he's not in Stockholm — Parker Smith / PR Newswire, © HHMI

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Mapping mRNAs in the brain

If the brain acts like a computer, which of the brain’s physical features store the information? Flashes of electricity may keep memories and sensations alive for the moment, but what plays the role that hard drives and CDs do for computers?

A simple answer could be: genes turning on and off, and eventually, neurons growing and changing their shapes. But it gets more complicated pretty quickly. Genes can be regulated at several levels:

  • at the level of transcription — whether messenger RNA gets made from a stretch of DNA in the cell’s nucleus
  • at the level of translation — whether the messenger RNA is allowed to make a protein
  • at the level of RNA localization — where the mRNAs travel within the cell

Each neuron has only two copies of a given gene but will have many dendrites that can have more or less RNA in them. That means the last two modes of regulation offer neurons much more capacity for storing information.

Gary Bassell, a cell biologist at Emory, and his colleagues have been exploring how RNA regulation works in neurons. They have developed special tools for mapping RNA, and especially, microRNA — a form of RNA that regulates other RNAs.

In the dendrites of neurons, FMRP seems to control where RNAs end up

In the dendrites of neurons, FMRP seems to control where RNAs end up

Fragile X mental retardation protein (FMRP), linked to the most common inherited form of mental retardation, appears to orchestrate RNA traffic in neurons. Bassell and pharmacologist Yue Feng recently received a grant from the National Institute of Child Health and Development to study FMRP’s regulation of RNA in greater detail. The grant was one of several at Emory funded through the American Recovery and Reinvestment Act’s support for the NIH.

In the video interview above, Bassell explains his work on microRNAs in neurons. Below is a microscope image, provided by Bassell, showing the pattern of FMRP’s localization in neurons.

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