Antibody production: an endurance sport

To understand recent research from immunologist Jerry Boss’s lab on antibody production, think about the distinction between sprinting and long-distance Read more

Less mucus, more neutrophils: alternative view of CF

A conventional view of cystic fibrosis (CF) and its effects on the lungs is that it’s all about mucus. Rabin Tirouvanziam has an alternative view, centered on Read more

Department of Pathology and Laboratory Medicine

FMT microbial transplant for C diff gaining acceptance

In February, the Infectious Diseases Society of America issued new guidelines for fighting Clostridium difficile, the hardy bacterium that can cause life-threatening diarrhea and whose dominance is sometimes a consequence of antibiotic treatment. The guidelines recommend for the first time that FMT (fecal microbiota transplant) be considered for individuals who have repeatedly failed standard antibiotics.

In a nice coincidence, Emory FMT specialists Colleen Kraft and Tanvi Dhere recently published a look at their clinical outcomes with C diff going back to 2012, in Clinical Infectious Diseases. They report 95 percent of patients (122/128) indicated they would undergo FMT again and 70 percent of the 122 said they would prefer FMT to antibiotics as initial treatment if they were to have a recurrence. Read more

Posted on by Quinn Eastman in Immunology Leave a comment

Exotic immune systems are big business

What timing! Just when our feature on Max Cooper and lamprey immunology was scheduled for publication, the Japan Prize Foundation announced it would honor Cooper and his achievements.

Cooper was one of the founders of modern immunology. We connect his early work with his lab’s more recent focus on lampreys, primitive parasites with surprisingly sophisticated immune systems.

Molecules from animals with exotic immune systems can be big business, as Andrew Joseph from STAT News points out. Pharmaceutical giant Sanofi recently bought a company focused on nanobodies, originally derived from camels, llamas and alpacas, for $4.8 billion.

Lampreys’ variable lymphocyte receptors (VLRs) are their version of antibodies, even though they look quite different in molecular terms. Research on VLRs and their origins may seem impractical. However, Cooper’s team has shown their utility as diagnostic tools, and his colleagues have been weaponizing them, possibly for use in cancer immunotherapy.

CAR-T cells have attracted attention for dramatic elimination of certain types of leukemias from the body and also for harsh side effects and staggering costs; see this opinion piece by Georgia Tech’s Aaron Levine. Now many research teams are scheming about how to apply the approach to other types of cancers. The provocative idea is: replace the standard CAR (chimeric antigen receptor) warhead with a lamprey VLR.

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Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Tug of war between Parkinson’s protein and growth factors

Alpha-synuclein, a sticky and sometimes toxic protein involved in Parkinson’s disease (PD), blocks signals from an important brain growth factor, researchers have discovered.

The results were published this week in PNAS.

The finding adds to evidence that alpha-synuclein is a pivot for damage to brain cells in PD, and helps to explain why brain cells that produce the neurotransmitter dopamine are more vulnerable to degeneration.

Alpha-synuclein is a major component of Lewy bodies, the protein clumps that are a pathological sign of PD. Also, duplications of or mutations in the gene encoding alpha-synuclein drive some rare familial cases.

In the current paper, researchers led by Keqiang Ye, PhD demonstrated that alpha-synuclein binds and interferes with TrkB, the receptor for BDNF (brain derived neurotrophic factor). BDNF promotes brain cells’ survival and was known to be deficient in Parkinson’s patients. When applied to neurons, BDNF in turn sends alpha-synuclein away from TrkB.  [Ye’s team has extensively studied the pharmacology of 7,8-dihydroxyflavone, a TrkB agonist.]

A “tug of war” situation thus exists between alpha-synuclein and BDNF, struggling for dominance over TrkB. In cultured neurons and in mice, alpha-synuclein inhibits BDNF’s ability to protect brain cells from neurotoxins that mimic PD-related damage, Ye’s team found. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Drug discovery: Alzheimer’s and Parkinson’s spurred by same enzyme

Alzheimer’s disease and Parkinson’s disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That’s how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson’s.

Keqiang Ye, PhD

In both Alzheimer’s (AD) and Parkinson’s (PD), a sticky and sometimes toxic protein forms clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies. Here is a thorough review of alpha-synuclein’s role in Parkinson’s disease.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it both more sticky and more toxic. In addition, they have found that AEP similarly processes beta-amyloid, another bad actor in Alzheimer’s, and drugs that inhibit AEP have beneficial effects in Alzheimer’s animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein as it does toward tau.

“In Parkinson’s, alpha-synuclein behaves much like Tau in Alzheimer’s,” Ye says. “We reasoned that if AEP cuts Tau, it’s very likely that it will cut alpha-synuclein too.”

A particular chunk of alpha-synuclein produced by AEP’s scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye’s team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can’t cut it is less toxic. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Urine tests for prostate cancer could reduce biopsies

In the prostate cancer field, there has been a push to move beyond PSA testing. With urine tests, it may be possible to avoid biopsies for men with suspected prostate cancer.

Martin Sanda, MD is chair of urology and leads Winship’s prostate cancer program

With PSA testing to guide decisions, only one in five men is found via biopsy to have a cancer that is sufficiently aggressive (Gleason score of 7 or higher) to warrant treatment right away.

A recently published paper in JAMA Oncology from urologist Martin Sanda and colleagues in the NCI’s Early Detection Research Network shows the potential of urine testing. Sanda’s team reports that two prostate cancer RNA biomarkers detectable in urine (PCA3 and T2:ERG) could be combined to enhance their discriminatory power and reduce unnecessary biopsies by almost half.

The National Cancer Institute’s Cancer Currents blog has an extensive discussion of the JAMA Oncology paper. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Amyloid vs tau? With this AD target, no need to choose

Keqiang Ye’s lab at Emory recently published a paper in Nature Communications that offers a two for one deal in Alzheimer’s drug discovery.

Periodically we hear suggestions that the amyloid hypothesis, the basis of much research on Alzheimer’s disease, is in trouble. Beta-amyloid is a toxic protein fragment that accumulates in extracellular brain plaques in Alzheimer’s, and genetics for early-onset Alzheimer’s point to a driver role for amyloid too.

In mice, inhibiting AEP hits two targets (amyloid and tau) with one shot

Unfortunately, anti-amyloid agents (either antibodies that sop up beta-amyloid or drugs that steer the body toward making less of it) have not shown clear positive effects in clinical trials.

That may be because the clinical trials started too late or the drugs weren’t dosed/delivered right, but there is a third possibility: modifying amyloid by itself is not enough.

Ye’s lab has been investigating an enzyme called AEP (asparagine endopeptidase), which he provocatively calls “delta secretase.” AEP is involved in processing both amyloid and tau, amyloid’s intracellular tangle-forming counterpart. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Fecal transplant replants microbial garden

When facing a life-threatening infection, the “yuck factor” is a minor concern. Fecal microbiota transplant (FMT for short) has become an accepted treatment for recurrent Clostridium difficile infection, which can cause severe diarrhea and intestinal inflammation.

In a new video, Emory physicians Colleen Kraft and Tanvi Dhere explain how FMT restores microbial balance when someone’s internal garden has been disrupted.

C. difficile or “C diff” is a hardy bacterium that can barge into the intestines after another infection has been treated with antibiotics, when competition for real estate is low. In the last few years, doctors around the world have shown that FMT can resolve recurrent C diff infection better than antibiotics alone.

At Emory, Kraft and Dhere have performed almost 300 FMTs and report a 95 percent success rate when treating recurrent C diff. They have established a standard slate of stool donors, whose health is carefully screened.

Building on their experience with the procedure, Kraft and Dhere are studying whether FMT can head off other antibiotic-resistant infections besides C diff in kidney transplant patients. They have teamed up with infectious disease specialists Aneesh Mehta and Rachel Friedman-Moraco to conduct this study. Read more

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Parkinson’s disease: hold the AMPs

Pathologist Keqiang Ye and colleagues recently published a paper in PNAS that may have implications for Parkinson’s disease pathology and treatment strategies.

The protein alpha-synuclein is a bad actor in PD (nice explainer from Michael J. Fox Foundation); it’s a major constituent of Lewy bodies, the protein clumps that appear in PD patients’ brains, and there is a genetic link too. Alpha-synuclein seems to bring other proteins into the clumps, which may disrupt neuron function.

In particular, it sequesters PIKE-L, an inhibitor of AMP kinase, leading to AMP kinase hyperactivation and cell death. AMP kinase is a metabolic regulator activated by metformin, a common treatment for diabetes. So activating AMP kinase in some situations can be good for your body; however for the neurons affected by alpha-synuclein, activating it too much is bad.

Posted on by Quinn Eastman in Neuro Leave a comment

Lampreys and the reverse spy problem

Call it the reverse spy problem. If you were a spy who wanted to gain access to a top secret weapons factory, your task would be to fit in. The details of your employee badge, for example, should look just right.

As described in this 2016 JCI Insight paper, Emory and University of Toronto investigators wanted to do the opposite. They were aiming to develop antibody tools for studying and manipulating plasma cells, which are the immune system’s weapons factories, where antibody production takes place. The situation is flipped when we’re talking about antibodies. Here, the goal is to stand out.

Do these guys look like good spies?

Monoclonal antibodies are classic biomedical tools (and important anticancer drugs). But it’s tricky to develop antibodies against the places where antibodies themselves are made, because of the way the immune system develops. To guard against autoimmune disease, antibodies that would react against substances in the body are often edited out.

To get around this obstacle, researchers used organisms that have very different immune systems from humans: lampreys. Emory’s Max Cooper and colleagues had already shown how lampreys have molecules — variable lymphocyte receptors or VLRs — that function like antibodies, but don’t look like them, in terms of their molecular structure.

From the paper:

We reasoned that the unique protein architecture of VLR Abs and the great evolutionary distance between lampreys and humans would allow the production of novel VLRB Abs against biomedically relevant antigens against which conventional Abs are not readily produced because of structural or tolerogenic constraints.

Senior author Goetz Ehrhardt, now at University of Toronto, used to be in Cooper’s lab, and their two labs worked together on the JCI Insight paper. Read more

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SIV remission follow-up

The surprising finding that an antibody treatment can push SIV-infected monkeys into prolonged remission, even after antiviral drugs are stopped, continues to rumble across the internet.

siv-a4b7-teaser-copy

Blue circles show how viral levels stayed low even after antiretroviral drugs were stopped.

The Science paper was featured on NIH director Francis Collins’ blog this week. NIAID director Anthony Fauci has been giving presentations on the research, which emerged from a collaboration from his lab and Tab Ansari’s at Emory. Fauci’s talk at the recent HIV prevention meeting in Chicago is viewable here.

At Lab Land, we were pleased to see that the watchdogs at Treatment Action Group had this to say:

“Media coverage of the paper has generally been accurate, but has had to wrestle with the uncertainty that exists among scientists regarding how ART-free control of viral load should be described.”

HIV pioneer Robert Gallo noted in an article accompanying the Science paper that the anti-integrin antibody treatment represents an emerging alternative to the vaunted “shock and kill” strategy, which he termed “soothe and snooze.” Note to reporters: the upcoming “Strategies for an HIV cure” conference at NIH in mid-November might be a good chance to compare the different strategies and put them in perspective.

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