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January 2013 Archives

Antiviral Drug Triggers Cell to Eat Itself

A chief weapon cells possess against infection is the ability to commit suicide. Obviously, suicide kills the cell, but it usually kills the invading microbe, as well. Thus, in multicellular organisms, individual cells "take one for the team" -- ending their own lives for the benefit of the organism as a whole, and the cell has multiple suicide options at its disposal.

Apoptosis is the best-known mechanism of cellular suicide. (Note: The second "p" is silent.) While apoptosis is often associated with developmental purposes (e.g., a tadpole losing its tail as it becomes an adult frog), this mechanism also serves an important immune function: Cytotoxic T-cells can trigger apoptosis in body cells which have become infected. For the most part, the death is quick and silent: the DNA is chopped up, and the cell shrivels and fragments into many pieces which are gobbled up by phagocytes.

Pyroptosis is a bit different. (Yes, the second "p" is silent here, too.) Think of "pyromaniacs" -- the people who set fires on purpose. Death by pyroptosis is sort of like that. An infected cell goes out with a bang, triggering inflammation and letting the immune system know that something horrible just happened. It serves as something of a wake-up call, moving the immune system to action.

Or... a cell could eat itself. This option is called autophagy, and like apoptosis, it is often associated with normal developmental processes and fighting infections. The cell fragments into small pieces internally and digests itself from within. Whatever is left over is cleaned up by phagocytes.

Now, researchers report in Nature the discovery of a potential therapeutic agent that triggers autophagy in virus-infected cells.

Aedes_aegypti_biting_human.jpgThe authors found that a peptide (short protein) called Tat-Beclin 1 was a strong inducer of autophagy. If applied to HeLa cells infected with three different viruses (Sindbis, Chikungunya, or West Nile -- all of which are transmitted by mosquitoes), the peptide greatly reduced the ability of the viruses to reproduce. The peptide also greatly reduced the ability of HIV to replicate in human macrophage cells. 

Encouraged by these results, the authors moved into a live mouse model, using the Chikungunya and West Nile viruses. The authors wanted to determine if triggering autophagy with Tat-Beclin 1 would rescue mice given a lethal dose of virus. Indeed, it worked, albeit modestly. Both viruses killed 100% of untreated mice. However, 37.5% of Chikungunya-infected and roughly 20% of West Nile-infected mice survived if treated with the therapeutic peptide.

These results clearly imply that autophagy inducing agents can be used as antivirals. Additionally, since autophagy also plays a role in normal developmental processes, the authors hope that autophagy inducing agents could be used to treat a wide variety of medical problems.

Source: Sanae Shoji-Kawata, et al. "Identification of a candidate therapeutic autophagy-inducing peptide." Nature 2013. Published online 30 Jan 2013. doi: 10.1038/nature11866

Background: Susan L. Fink and Brad T. Cookson. "Apoptosis, Pyroptosis, and Necrosis: Mechanistic Description of Dead and Dying Eukaryotic Cells." Infect Immun 2005. April; 73(4): 1907-1916. doi: 10.1128/IAI.73.4.1907-1916.2005

January 2013 Archives

Shock Block: Preventing Deaths in the ICU

We're all going to die, but some ways are more preferable than others. For instance, a woman in Washington State is suspected of smothering her boyfriend to death with her breasts. Me? I'd prefer that an anvil fall on my head (a la Wile E. Coyote) after my 100th birthday: quick and (probably) painless.

But, most of us won't be that lucky. In fact, each year in the U.S., hundreds of thousands of people die in intensive care units from circulatory shock, a condition in which insufficient oxygen and nutrients are delivered to the body's tissues. Left unchecked, shock can lead to organ dysfunction, which is often followed by that ultimately irreversible symptom: Death.

Intestinesbeforeaftertreatment.jpgShock has multiple causes. Two common types include hemorrhagic shock, which occurs following traumatic blood loss, and septic shock, which occurs following systemic bacterial infection. Both lead to hypovolemia (low blood volume) and hypotension (low blood pressure), which cause organ dysfunction.

Additionally, the intestines play a major role in shock, and it is thought that proteases (digestive enzymes) secreted by the pancreas break through the intestine's mucosal barrier, digesting the intestinal wall. Even worse, the enzymes can enter systemic circulation and damage other organs, greatly exacerbating the problem.

Researchers from UC-San Diego wanted to determine if blocking these enzymes could help rescue rats suffering from shock induced by blood loss, peritonitis (abdominal inflammation due to infection) or endotoxin (a bacterial membrane molecule which causes septic shock). They found that injecting enzyme inhibitors directly into the small intestine greatly increased survival and decreased organ damage. (See figure. Top panel: Normal intestines; middle panel: shock; bottom panel: shock + enzyme inhibitors.) Damage to the lungs and heart was also reduced when the rats were treated with enzyme inhibitors.

Given the success observed in the rat model, the authors hope to see the same in human patients.

Source: F. A. DeLano, D. B. Hoyt, G. W. Schmid-Schönbein. "Pancreatic Digestive Enzyme Blockade in the Intestine Increases Survival After Experimental Shock." Sci Transl Med 5, 169ra11 (2013).

Source and image source: "Blocking Digestive Enzymes May Reverse Shock, Stop Multiorgan Failure." UCSD press release. January 23, 2013.
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January 2013 Archives

Immunological Wisdom from 'The Three Stooges'

Fans of The Three Stooges may remember the episode in which Curly asks Moe what he wants to eat. Moe responds, "Four pieces of burnt toast and a rotten egg." Why did he say this? Because Moe had a "tapeworm and it's good enough for him." Little did Moe know that he was actually dispensing profoundly deep immunological wisdom. 

This week, scientists from the University of Michigan and the University of Manchester reported in the journal PLoS Pathogens that, when faced with a parasitic infection, a mouse's immune system will purposefully cause it to undereat (i.e., "hypophagia"). To show this, they infected normal mice and mice that had various immunological deficiencies with the roundworm Trichinella spiralis. (This parasite causes trichinosis, an infection associated with undercooked pork.) 
Trichinella_larv1_DPDx.JPG

The researchers demonstrated that a mouse infected with T. spiralis has a two-phase hypophagic response. Both phases of reduced eating were dependent on a functioning adaptive immune response (which generates antibodies). Mice that lacked an adaptive immune response ate normally. That might not sound like a terrible thing, but it didn't work out well for the mice. 

Typically, when mice don't eat, blood levels of a metabolism-regulating hormone called leptin decrease. Leptin also happens to regulate the immune response. With less leptin around, the mouse is able to direct its immune system toward producing antibodies. But if levels of leptin are too high, the mouse appears less able to do that.

Connecting all this, the authors hypothesized that leptin was the key factor. They believe that mice purposefully quit eating so that their leptin levels drop, allowing the mouse to generate a robust antibody response against the parasite. To test this, they injected leptin into mice infected with T. spiralis. Just as they expected, the mice had a very difficult time fighting off the parasite.

Altogether, the researchers demonstrated that undereating is not just a side effect of parasitic infection; instead, it is vital to fighting off the worm.

And you thought there was no intellectual value in watching The Three Stooges. Nyuk nyuk nyuk

(This post is dedicated to my dad, who still watches Moe, Larry and Curly.)

Source: Worthington JJ, Samuelson LC, Grencis RK, McLaughlin JT (2013) Adaptive Immunity Alters Distinct Host Feeding Pathways during Nematode Induced Inflammation, a Novel Mechanism in Parasite Expulsion. PLoS Pathog 9(1): e1003122. doi:10.1371/journal.ppat.1003122

(Image: Trichinella spiralis via Wikimedia Commons)
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January 2013 Archives

Disease, Biodiversity & the Wealth of Nations

One of the foundational books of modern economics is An Inquiry into the Nature and Causes of the Wealth of Nations by Adam Smith. Smith elaborates on topics ranging from currency to division of labor, and also discusses the oft quoted concept of the "invisible hand" which guides the marketplace to efficient outcomes. According to Smith and many economists, the wealth of nations is primarily derived from political and economic institutions.

But what if that is only part of the equation? It has long been observed that there is a correlation between geography and wealth, namely, countries close to the equator are poor, while countries far from the equator are rich. (See first figure.) 
Geography-GDP.jpg
Several explanations have been proposed, one of which is infectious disease. Countries near the equator must cope with diseases, such as malaria, that countries far from the equator do not. That's because malaria-carrying mosquitoes can survive year round in the tropics, but only thrive seasonally in more temperate climates. With this in mind, is it possible that basic biology is one of the driving forces behind economic growth?

The connection between biology and economics was explored in greater depth in a recent PLoS Biology paper.

One of the difficulties in investigating the cause of economic poverty is that multiple factors simultaneously influence each other. In this case, poverty causes an inability to deal with infectious disease, and a greater burden of disease causes more poverty. Yet, determining how and to what extent disease can directly affect economic outcomes is more than just an academic exercise. It may very well be that providing adequate health care to poor countries is a necessary part of any economic development plan. 

The authors attempted to determine the relationship between disease (specifically parasitic and vector-borne diseases, which are typically endemic) and per capita income. They also examined another crucial factor: The role biodiversity plays in disease burden. To do this, the authors constructed a statistical model which included data on disability due to vector-borne diseases, per capita income, biodiversity, the effectiveness of governing institutions, and various features of geography.

As expected, the authors found that a greater burden of disease correlates with lower per capita income. Perhaps unexpectedly, after controlling for other variables, the authors found that greater biodiversity correlates with a lower disease burden. (See second figure; y-axis represents disease burden.) Presumably, greater biodiversity causes problems for human pathogens. For example, if there are more types of birds around, more malaria-carrying mosquitoes will get eaten. 
Biodiversity-Disease.jpg
Combined, the above findings imply that increasing biodiversity could help increase per capita income.

Additionally, these results suggest that preserving biodiversity -- while a worthy goal in and of itself -- is incredibly relevant to the livelihoods of people. Indeed, a healthier ecosystem may allow for a wealthier planet.

Source: Bonds MH, Dobson AP, Keenan DC (2012). Disease Ecology, Biodiversity, and the Latitudinal Gradient in Income. PLoS Biol 10(12): e1001456. doi:10.1371/journal.pbio.1001456

Source: Disease Burden Links Ecology to Economic Growth (Press Release).
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January 2013 Archives

Admitting You're Wrong Is Hard to Do

They say that breaking up is hard to do, but what's infinitely harder is to admit when you're wrong. When somebody publicly issues a heartfelt mea culpa, many people wrongly celebrate with an "I told you so" dance. However, that's not the proper response. Celebrating is okay, as long as we celebrate the "conversion" and welcome the person into the fold. 

Yesterday, Slate reported that long-time anti-GMO activist Mark Lynas admitted he was wrong about genetically modified food. His opening remarks were particularly poignant:

I want to start with some apologies. For the record, here and upfront, I apologise for having spent several years ripping up GM crops. I am also sorry that I helped to start the anti-GM movement back in the mid 1990s, and that I thereby assisted in demonising an important technological option which can be used to benefit the environment.

As an environmentalist, and someone who believes that everyone in this world has a right to a healthy and nutritious diet of their choosing, I could not have chosen a more counter-productive path. I now regret it completely.

Wow! That takes guts. He goes on:

What happened...that made me not only change my mind but come here and admit it? Well, the answer is fairly simple: I discovered science, and in the process I hope I became a better environmentalist.

shutterstock_70521655.jpgChanging your mind when the data doesn't support your opinion is vital not only to being a good scientist or journalist, but a good human being. Indeed, as RealClearScience assistant editor Ross Pomeroy wrote, it is one of the keys to life. Because many facts have a half-life, all of our opinions should be subject to change. Besides, as astrophysicist Ethan Siegel correctly noted, there is tremendous power in admitting that you're wrong.

But Mr. Lynas wasn't the only one to issue a high-profile mea culpa in recent times. Here are some other famous "my bads" from 2012:

  • Physicist Richard Muller, author of the BEST study, now believes that humans are the primary drivers of climate change. He even refers to himself as a "converted skeptic."
  • Psychiatrist Robert Spitzer apologized for promoting the idea that gay people could be "cured."
  • Two political scientists admitted their model was wrong after they incorrectly forecasted a Romney victory in 2012 based on economic data.

Admitting wrongness is such an admirable quality that all of us should make it our (belated) New Year's resolution for 2013. 

Then, just maybe, there wouldn't be so many people breaking up in the first place.

(Image: Wrong via Shutterstock)