Quinn Eastman

Neuroinflammation: a different way to look at Parkinson’s disease

Emory physiologist Malu Tansey and her colleagues are using recent insights into the role of inflammation in Parkinson’s disease to envision new treatments. One possible form this treatment strategy could take would be surprisingly simple, and comparable to medications that are approved for rheumatoid arthritis.

Malu Tansey, PhD

Understanding the role of inflammation in Parkinson’s requires a shift in focus. Many Parkinson’s researchers understandably emphasize the neurons that make the neurotransmitter dopamine. They’re the cells that are dying or already lost as the disease progresses, leading to tremors, motor difficulties and a variety of other symptoms.

But thinking about the role of inflammation in Parkinson’s means getting familiar with microglia, the immune system’s field reps within the brain. At first, it was thought that the profusion of microglia in the brains of Parkinson’s patients was just a side effect of neurodegeneration. The neurons die, and the microglia come in to try to clean up the debris.

Now it seems like microglia and inflammation might be one of the main events, if not the initiating event.

“Something about the neurons’ metabolic state, whether it’s toxins, oxidative stress, unfolded proteins, or a combination, makes them more sensitive. But inflammation, sustained by the presence of microglia, is what sends them over the edge,” Tansey says.

She says that several recent studies have led to renewed attention to this area:

  1. In vivo PET imaging using a probe for microglia has allowed scientists to see inflammation starting early in the progression of Parkinson’s (see figure below)
  2. Epidemiology studies show that taking ibuprofen regularly is linked to lower incidence of Parkinson’s
  3. Experiments with animal models of genetic susceptibility demonstrate that inflammatory agents like endotoxin can accelerate neurodegeneration
  4. Genomics screens have identified HLA-DR, an immune system gene, as a susceptibility marker for Parkinson’s (Emory’s Stewart Factor was a co-author on this paper)

Popping a few ibuprofen pills everyday for prevention and possibly damaging the stomach along the way is probably not going to work well, Tansey says. It should be possible to identify a more selective way to inhibit microglia, which may be able to inhibit disease progression after it has started.

Activated microglia in the midbrain and striatum of a Parkinson's patient

Targeting TNF (tumor necrosis factor), an important inflammatory signaling molecule, may be one way to go. Anti-TNF agents are already used to treat rheumatoid arthritis and inflammatory bowel disease. This January, Tansey and her co-workers published a paper showing that a gene therapy approach using decoy TNF can reduce neuronal loss in a rat model of Parkinson’s. More recently, her lab has also shown that targeting the gene RGS10 is another way to inhibit microglia and reduce neurodegeneration in the same models.

It is important to note that in the rat studies, they do surgery and put the gene therapy viral vector straight into the brain. She says it might possible to perform peripheral gene therapy with the microglia, or even anti-TNF medical therapy. In terms of mechanism, decoy (technically, dominant negative) TNF is more selective and may avoid the side effects, such as opportunistic infections, of existing anti-TNF agents.

Posted on by Quinn Eastman in Neuro 1 Comment

Excitement building over potential for universal flu vaccine

Francis Collins, director of the National Institutes of Health, made a splash last week predicting the arrival of a universal flu vaccine in the next five years.

Francis Collins told USA Today he is "guardedly optimistic" about the possibility of long-term vaccination that could replace seasonal flu shots.

His prediction came at the same time as a report in Science identifying an antibody that can protect against several strains of the flu virus. Taking a look at the Science paper, how the scientists found the “super antibody” seems remarkably similar to how Emory’s Jens Wrammert, Rafi Ahmed and colleagues found a similar broadly protective antibody. Their results were published in the Journal of Experimental Medicine in January.

In both cases, the researchers started with someone who had been infected with the 2009 H1N1 swine origin flu virus, sifted through the antibodies that person produced and found some that reacted against several varieties of the flu virus. There must be something special about that 2009 pandemic strain!

Posted on by Quinn Eastman in Immunology Leave a comment

Dispelling confusion about probiotic bacteria

While humans have been consuming fermented foods such as yogurt and kimchi for centuries, a visitor to a modern grocery store can see the recent commercial enthusiasm for adding probiotic bacteria to foods. A recent article in Slate explores the confusion over potential health benefits for these added bacteria.

The bacteria that live inside us seem to play an important role regulating metabolism, the immune system and the nervous system, but scientists have a lot to learn about how those interactions take place.

Researchers at Emory have been clarifying exactly how probiotic bacteria promote intestinal health. Andrew Neish and his colleagues have found that the bacteria give intestinal cells a little bit of oxidative stress, which is useful for promoting the healing of the intestinal lining.

Beneficial bacteria induce reactive oxygen species production by intestinal cells, which promotes wound healing.

Posted on by Quinn Eastman in Immunology Leave a comment

Autism linked to hundreds of spontaneous genetic mutations

Emory genetic researchers Daniel Moreno De Luca, Christa Lese Martin and David Ledbetter were part of a team that produced a landmark result in autism genetics. The team identified hundreds of regions of the genome where spontaneous mutations are implicated in autism. Spontaneous mutations are those that arise for the first time in an individual, rather than being inherited from parents.

Christa Lese Martin, PhD

The team was led by Matthew State at Yale, and their results were published in the journal Neuron. Moreno De Luca discussed the topic in Spanish on a recent edition of the NPR program Science Friday. The June 10 segment was focused on autism genetics.

The team made an intriguing finding on a segment of chromosome 7. Deletion of the region is associated with Williams syndrome, where individuals can exhibit “striking verbal abilities, highly social personalities and an affinity for music.” Duplication of the same region, they found, is associated with autism.

Daniel Moreno De Luca, MD MSc

Companion studies also shed light on the question of why boys are more likely to develop autism than girls, and begin to outline a network of genes whose activity is altered in the brains of individuals with autism.

Ledbetter is now chief scientific officer at Geisinger Health in Pennsylvania.

 

 

 

Posted on by Quinn Eastman in Neuro Leave a comment

Default daydreaming linked to Alzheimer’s amyloid

Cut the daydreaming, and you can lessen the neurodegenerative burden on your brain? Surprising new research suggests that how we use our brains may influence which parts of the brain are most vulnerable to amyloid-beta (Aβ), which forms plaques in the brain in Alzheimer’s disease.

Lary Walker, PhD, has been investigating why amyloid accumulation seems to lead to Alzheimer's in humans but not non-human primates

In the June issue of Nature Neuroscience, Yerkes National Primate Research Center scientist Lary Walker and Mathias Jucker from the Hertie Institute for Clinical Brain Research in Tübingen, Germany summarize intriguing recent research on regional brain activity and Aβ accumulation.

Neuroscientists have described a set of interconnected brain regions called the “default mode network,” which appear to be activated during activities such as introspection, memory retrieval, daydreaming and imagination. When a person engages in an externally directed task, such as reading, playing a musical instrument, or solving puzzles, activity in the default network decreases.

The Nature Neuroscience paper, from David Holtzman and colleagues at Washington University St. Louis, suggests prolonged metabolic activation of the default-mode network in mice can render that system vulnerable to Aβ by accelerating Aβ deposition and plaque growth.

This line of research turns the “use it or lose it” idea upside-down. Use the default network too much, and the effect may be harmful. Walker and Jucker suggest why education, for example, appears to head off Alzheimer’s in epidemiological studies: by getting the brain involved in non-default/externally directed mode activity.

This idea has additional consequences that can be tested in the clinic. For example, by increasing metabolism in default-mode regions of the brain, prolonged wakefulness caused by sleep disorders might increase Aβ burden.

Walker and Jucker conclude: “Meanwhile, perhaps the best strategy for lessening soluble Aβ in the default mode network may be simply to work diligently, play hard and sleep well.”

 

Posted on by Quinn Eastman in Neuro 2 Comments

Low vitamin D in people with HIV: links to heart risk, immune function

In people with HIV, low vitamin D levels have been linked to thicker carotid arteries as well as a weaker comeback for the immune system after starting antiretroviral therapy.

These results, published online recently in the journal Antiviral Therapy, are the first to confirm an association between low vitamin D levels and a measure of higher cardiovascular risk in people with HIV. They also suggest that the benefits of vitamin D supplementation for people with HIV should be evaluated in a clinical trial.

Allison Ross, MD, is an infectious disease specialist in the Department of Pediatrics and the Emory-Children's Pediatric Research Center.

The advent of effective antiretroviral therapy against HIV has dramatically improved life expectancies for people with HIV over the last 15 years. The presence of HIV is known to perturb cardiovascular health, even in the absence of an active infection. Since vitamin D levels are known to have an impact on the immune system and cardiovascular disease risk, that drove infectious disease specialist Allison Ross and her colleagues to probe these connections in people living with HIV. The results were also described on the Web sites AidsMeds and NAM/AidsMap.

Ross studied a group of HIV-positive people enrolled in Case Western Reserve University’s HIV clinic in Cleveland. Colleagues from Emory and Case Western were co-authors.

They tested vitamin D levels, immune function and heart health in 149 HIV-positive people and a matched group of 34 HIV-negative people. Vitamin D levels were significantly lower in the HIV-positive group, even when controlling for known factors that affect vitamin D.

The researchers looked at how much the immune system was able to come back after starting retroviral therapy. This involves comparing someone’s lowest ever CD4 T cell count from the current CD4 count. They found that people with the poorest level of immune restoration were the most likely to have the lowest level of vitamin D. In addition, people with the lowest vitamin D levels were more than 10 times as likely to have thickening of the carotid arteries, as measured by ultrasound.

Inflammation can be a driving factor for heart disease, but in the study, low vitamin D was not linked to higher levels of inflammation markers. Additional research could determine whether those who are starting antiretroviral therapy would see better immune recovery if they took a vitamin D supplement.

Researchers at Emory have been investigating several aspects of low Vitamin D levels and their impact on health, including a connection with Parkinson’s disease. Endocrinologist Vin Tangpricha notes that Emory studies are looking at vitamin D in the context of tuberculosis, sepsis, sickle cell disease, cancer, cystic fibrosis and pain sensitivity.

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What cancer researchers can learn from fruit fly genetics

What can scientists studying cancer biology learn from fruit flies?

Quite a lot, it turns out.  At a time when large projects such as the Cancer Genome Atlas seek to define the changes in DNA that drive cancer formation, it is helpful to have the insight gained from other arenas, such as fruit flies, to make sense of the mountains of data.

Drosophila melanogaster has been an important model organism for genetics because the flies are easy to care for, reproduce rapidly, and have an easily manipulated genome. This NCI newsletter article describes how some investigators have used Drosophila to find genes involved in metastasis.

Emory cell biologist Ken Moberg says that he and postdoctoral fellow Melissa Gilbert crafted a Drosophila-based strategy to identify growth-regulating genes that previous researchers may have missed. Their approach allowed them to begin defining the function of a gene that is often mutated in lung cancer. The results are published online in Developmental Cell.

Part of the developing fly larva, stained with an antibody against Myopic. Groups of cells lacking Myopic, which lack green color, tend to divide more rapidly.

Moberg writes:

Many screens have been carried out in flies looking for single gene lesions that drive tissue overgrowth. But a fundamental lesson from years of cancer research is that many, and perhaps most, cancer-causing mutations also drive compensatory apoptosis, and blocking this apoptosis is absolutely required for cancer outgrowth.

We reasoned that this class of ‘conditional’ growth suppressor genes had been missed in prior screens, so we designed an approach to look for them. The basic pathways of apoptosis are fairly well conserved in flies, so it’s fairly straight forward to do this.

Explanatory note: apoptosis is basically a form of cellular suicide, which can arise when signals within the cell clash; one set of proteins says “grow, grow” and another says “brake, brake,” with deadly results.

Gilbert identified the fruit fly gene Myopic as one of these conditional growth regulators. She used a system where mutations in Myopic drive some of the cells in the fly’s developing eye to grow out more – but only when apoptosis is disabled.

Gilbert showed that Myopic is part of a group of genes in flies, making up the Hippo pathway, which regulates how large a developing organ will become. This pathway was largely defined in flies, then tested in humans, Moberg says. The functions of the genes in this pathway have been maintained so faithfully that in some cases, the human versions can substitute for the fly versions.

Myopic’s ortholog (ie different species, similar sequence and function) is the gene His-domain protein tyrosine phosphatase, or HD-PTP for short. This gene is located on part of the human genome that is deleted in more than 90 percent of both small cell and non-small cell lung cancers, and is also deleted in renal cancer cells.

How HD-PTP, when it is intact, controls the growth of cells in the human lung or kidney is not known. Gilbert and Moberg’s findings suggest that HD-PTP may function through a mechanism that is similar to Myopic’s functions in the fly.

Besides clarifying what Myopic does in the fly, their paper essentially creates a map for scientists studying HD-PTP’s involvement in lung cancer, for example, to probe and validate.

Posted on by Quinn Eastman in Cancer 1 Comment

Nitrite: from cured meat to protected heart

Nitrite may be best known as a food additive used in cured meats such as hot dogs, but medical researchers are studying how it could treat several conditions, including preventing damage to the heart after a heart attack.

Leaders in the nitrite field are meeting May 11 -13, 2011 at Emory Conference Center in Atlanta. One of the lead organizers is David Lefer, PhD, professor of surgery at Emory University School of Medicine and director of the Cardiothoracic Research Laboratory. Lefer discusses the beneficial effects of nitrite in the video below. More information about the meeting is available here.

Scientists think supplying a pulse of nitrite can reduce injury to heart tissue coming from the interruption of blood flow. Several clinical trials are now investigating nitrite as a therapy for conditions such as heart attack, ruptured aneurysm, sickle cell pain crisis and cardiac arrest.

Nitrite acts as the body’s reserve for nitric oxide, which turns on chemical pathways that relax blood vessels. Delivering nitric oxide directly into the body is expensive and hard to control. Unlike nitric oxide, whose lifetime in the body is a few seconds, nitrite is stable and stored in the body’s tissues and can be delivered in a variety of ways. It is converted into nitric oxide under conditions when the body needs it: lack of blood or oxygen. In addition, sodium nitrite has been used as part of a cyanide antidote kit. This means that safety data on large doses of nitrite in critically ill people is available.

In a 2005 paper published in the Journal of Clinical Investigation, Lefer and colleagues showed that nitrite can reduce damage to the hearts of mice after a simulated heart attack. More recently, assistant professor John Calvert and Lefer have shown that internally generated and stored nitrite is an important way that exercise protects the heart from a heart attack.

Some blood pressure studies underway in Europe have participants consume large amounts of beet juice as their source of nitrate, which is then converted to nitrite in the body.

A wave of public concern about nitrite and its relative nitrate in the 1970s focused on their presence in cured meats and their ability to form nitrosamines, which can be carcinogenic. Subsequent investigation showed that actually, most of the nitrite and nitrate in the average adult’s diet come from vegetables such as broccoli and spinach, and that antioxidants such as vitamin C can prevent nitrosamine formation.

Nathan Bryan, a speaker at the conference from UT-Houston, was featured in a recent television news story about herbal supplements designed to boost nitrite in the body.

Posted on by Quinn Eastman in Heart 2 Comments

Brain enhancement: can and should we do it?

The Emory Center for Ethics and Emory’s Neuroscience Graduate Program recently co-hosted a symposium discussing the ethics of brain-enhancing technologies, both electronic and pharmacological.

Georgia Tech biomedical engineer Steve Potter explained his work harnessing the behavior of neurons grown on a grid of electrodes. The neurons, isolated from rats, produce bursts of electrical signals in various patterns, which can be “tuned” by the inputs they receive.

“The cells want to form circuits and wire themselves up,” he said.

As for future opportunities, he cited the technique of deep brain stimulation as well as clinical trials in progress, including one testing technology developed by the company Neuropace that monitors the brain’s electrical activity for the purpose of suppressing epileptic seizures. Similar technology is being developed to help control prosthetic limbs and could also promote recovery from brain injury or stroke, he said. Eventually, electrical stimulation that is not modulated according to feedback from the brain will be seen as an overly blunt instrument, even “barbaric,” he said.

Mike Kuhar, a neuroscientist at Yerkes National Primate Research Center, introduced the topic of cognitive enhancers or “smart drugs.” He described one particular class of proposed cognitive enhancers, called ampakines, which appear to improve functioning on certain tasks without stimulating signals throughout the brain. Kuhar questioned whether “smart drugs” pose unique challenges, compared to other types of drugs. From a pharmacology perspective, he said there is less distinction between therapy and enhancement, compared to a perspective imposed by regulators or insurance companies. He described three basic concerns: safety (avoiding toxicity or unacceptable side effects), freedom (lack of coercion from governments or employers) and fairness.

“Every drug has side effects,” he said. “There has to be a balance between the benefits versus the risks, and regulation plays an important role in that.”

He identified antidepressants and treatments for attention deficit-hyperactivity disorder or the symptoms of Alzheimer’s disease as already raising similar issues. The FDA has designated mild cognitive impairment associated with aging as an open area for pharmaceutical development, he noted.

James Hughes, a sociologist from Trinity College and executive director of the Institute for Ethics and Emerging Technologies, welcomed new technologies that he said could not only treat disease, but also enhance human capabilities and address social challenges such as criminal rehabilitation. However, he did identify potential “Ulysses problems”, where users of new technologies would need to exercise control and judgment.

In contrast, historian and Judaic scholar Hava Tirosh-Samuelson, from Arizona State University, decried an “overly mechanistic and not culturally-based understanding of what it means to be human.” She described transhumanism as a utopian extension of 19th century utilitarianism as expounded by thinkers such as Jeremy Bentham.

“Is the brain simply a computational machine?” she asked.

The use of military metaphors – such as “the war on cancer” – in the context of mental illness creates the false impression that everything is correctable or even perfectable, she said.

Emory neuroscience program director Yoland Smith said he wants ethics to become a strong component of Emory’s neuroscience program, with similar discussions and debates to come in future years.

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Talent in the pipeline

The Pipeline program, an initiative led by Emory medical students to improve college readiness and promote health career interest among Atlanta high school students, held graduation ceremonies Wednesday night at Emory University School of Medicine.

Graduating seniors and their mentors. All 19 seniors have at least one college acceptance, reports Pipeline co-founder Zwade Marshall.

Leaders at South Atlanta School of Health and Medical Sciences credit Pipeline with sparking interest in health science careers and bolstering attendance and academic performance.

“We see more leadership, not just in class but in the whole building,” says Edward Anderson, a teacher who coordinates the program. “Students are picking up the torch and running with it. I believe they will be future leaders and have a great impact.”

Sophomores, juniors, and seniors have access to a distinct curriculum with a classroom component, one-on-one mentoring by Emory undergraduates, and hands-on demonstrations. Sophomores explore infectious diseases and HIV/AIDS. Juniors study neuroscience. And seniors—who get help with college application coaching—focus on cardiology and community outreach, culminating in a health fair that they organize at their school.

Pipeline is run by Emory student volunteers with the support of the School of Medicine Office of Multicultural Medical Student Affairs, the Office of University-Community Partnerships, and the Emory Center for Science Education.

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