Friday, March 27, 2015

Fixing 'leaky' blood vessels to combat severe respiratory ailments and, perhaps, Ebola

When you get an infection, your immune system responds with an influx of inflammatory cells that target the underlying bacteria or viruses. These immune cells migrate from your blood into the infected tissue in order to release a cocktail of pro-inflammatory proteins and help eliminate the infectious threat. During this inflammatory response, the blood vessel barrier becomes “leaky.” This allows for an even more rapid influx of additional immune cells. Once the infection resolves, the response cools off, the entry of immune cells gradually wanes and the integrity of the blood vessel barrier is restored.

But if the infection is so severe that it overwhelms the immune response or if the patient is unable to restore the blood vessel barrier, fluid moves out of the blood vessels and begins pouring into the tissue. This “leakiness” is what can make pneumonia turn into acute respiratory distress syndrome. ARDS, by my estimate affects hundreds of thousands of people each year worldwide. In the US around 190,000 people develop ARDS each year and it has a mortality rate of up to 40%. In people with Ebola, this leakiness is also often deadly, causing severe blood pressure drops and shock.
New therapies to fix the leakiness of blood vessels in patients suffering from life-threatening illnesses, such as acute respiratory distress syndrome and Ebola virus infections, have the potential to save many lives.

What is ARDS?

Severe pneumonia can lead to acute respiratory distress syndrome (ARDS), a complication in which the massive leakiness of blood vessels in the lung leads to the fluid build-up, which covers the cells that exchange oxygen and carbon dioxide. Patients usually require mechanical ventilators to force oxygen into the lungs in order to survive.
Pneumonia is one of the most common causes of ARDS but any generalized infection and inflammation that is severe enough to cause massive leakiness of lung blood vessels can cause the syndrome.
For people with ARDS treatment, options other than ventilators and treating the underlying infection are limited. And suppressing the immune system to treat this leakiness can leave patients vulnerable to infection.

A new treatment option

But what if we specifically target the leakiness of the blood vessels? Our research has identified an oxygen-sensitive pathway in the endothelial cells which line the blood vessels of the lungs. The leakiness or tightness of the blood vessel barrier depends on the presence of junctions between these cells. These junctions need two particular proteins to work properly. One is called VE-cadherin and is a key building block of the junctions. The other is called VE-PTP and helps ensure that VE-cadherin stays at the cell surface where it can form the junctions with neighboring cells.
When the endothelial cells are inflamed, these junctions break down and the blood vessels become leaky. This prompts the cells to activate a pathway via Hypoxia Inducible Factors (HIFs), which are usually mobilized in response to low oxygen stress. In the heart, HIF pathways are activated during a heart attack or long-standing narrowing of the heart blood vessels to improve the survival of heart cells and initiate the growth of new blood vessels.

We found that a kind of HIF (called HIF2α) was protective in lung blood vessel cells. When it was activated, it increased levels of the proteins that support the junctions between lung cells and strengthened the blood vessel barrier. But in many patients, this activation may not start soon enough to prevent ARDS.

The good news is that we can activate this factor before the lung fluid accumulates and before low oxygen levels set in. Using a drug, we activated HIF2α under normal oxygen conditions, which “tricked” cells into initiating their protective low-oxygen response and tightening the blood vessel barrier. Mice treated with a HIF2α activation drug had substantially higher survival rates when exposed to bacterial toxins or bacteria which cause ARDS.

Similar drugs have already been used in small clinical trials to increase the production of red blood cells in anemic patients. This means that activating HIF2α is probably safe for human use and may indeed become a viable strategy in ARDS. However, the efficacy and safety of drugs which activate HIF2α still have to be tested in humans with proper placebo control groups.

Could this treat Ebola?

The Ebola virus is a hemorrhagic virus and is also known to induce the breakdown of blood vessel barriers. In fact, it is these leaks in the blood vessels that make the disease so deadly. Due to the leakage of fluid and blood from the blood vessels into the tissue, the levels of fluid and blood inside the blood vessels decrease to critically low levels, causing blood pressure drops and ultimately shock. A group of researchers in Germany recently reported the use of an experimental drug (a peptide) developed for the treatment of vascular leakage in a 38-year-old doctor who had contracted Ebola in Sierra Leone and was airlifted to Germany. The researchers received a compassionate-use exemption for the drug and the patient recovered.

This is just a single case report and it is impossible to know whether the patient would have recovered similarly well without the experimental vascular leakage treatment, but it does highlight the potential role of drugs which treat blood vessel leakiness in Ebola patients.

The Conversation

This article was originally published on The Conversation. Read the original article. Gong, H., Rehman, J., Tang, H., Wary, K., Mittal, M., Chatturvedi, P., Zhao, Y., Komorova, Y., Vogel, S., & Malik, A. (2015). HIF2α signaling inhibits adherens junctional disruption in acute lung injury Journal of Clinical Investigation, 125 (2), 652-664 DOI: 10.1172/JCI77701

Thursday, March 5, 2015

Does Thinking About God Increase Our Willingness to Make Risky Decisions?

There are at least two ways of how the topic of trust in God is broached in Friday sermons that I have attended in the United States. Some imams lament the decrease of trust in God in the age of modernity. Instead of trusting God that He is looking out for the believers, modern day Muslims believe that they can control their destiny on their own without any Divine assistance. These imams see this lack of trust in God as a sign of weakening faith and an overall demise in piety. But in recent years, I have also heard an increasing number of sermons mentioning an important story from the Muslim tradition. In this story, Prophet Muhammad asked a Bedouin why he was leaving his camel untied and thus taking the risk that this valuable animal might wander off and disappear. When the Bedouin responded that he placed his trust in God who would ensure that the animal stayed put, the Prophet told him that he still needed to first tie up his camel and then place his trust in God. Sermons referring to this story admonish their audience to avoid the trap of fatalism. Just because you trust God does not mean that it obviates the need for rational and responsible action by each individual.

It is much easier for me to identify with the camel-tying camp because I find it rather challenging to take risks exclusively based on the trust in an inscrutable and minimally communicative entity. Both, believers and non-believers, take risks in personal matters such as finance or health. However, in my experience, many believers who make a risky financial decision or take a health risk by rejecting a medical treatment backed by strong scientific evidence tend to invoke the name of God when explaining why they took the risk. There is a sense that God is there to back them up and provide some security if the risky decision leads to a detrimental outcome. It would therefore not be far-fetched to conclude that invoking the name of God may increase risk-taking behavior, especially in people with firm religious beliefs. Nevertheless, psychological research in the past decades has suggested the opposite: Religiosity and reminders of God seem to be associated with a reduction in risk-taking behavior.

 Daniella Kupor and her colleagues at Stanford University have recently published the paper "Anticipating Divine Protection? Reminders of God Can Increase Nonmoral Risk Taking" which takes a new look at the link between invoking the name of God and risky behaviors. The researchers hypothesized that reminders of God may have opposite effects on varying types of risk-taking behavior. For example, risk-taking behavior that is deemed ‘immoral' such as taking sexual risks or cheating may be suppressed by invoking God, whereas taking non-moral risks, such as making risky investments or sky-diving, might be increased because reminders of God provide a sense of security. According to Kupor and colleagues, it is important to classify the type of risky behavior in relation to how society perceives God's approval or disapproval of the behavior. The researchers conducted a variety of experiments to test this hypothesis using online study participants.

 One of the experiments involved running ads on a social media network and then assessing the rate of how often the social media users clicked on slightly different wordings of the ad texts. The researchers ran the ads 452,051 times on accounts registered to users over the age of 18 years residing in the United States. The participants either saw ads for non-moral risk-taking behavior (skydiving), moral risk-taking behavior (bribery) or a control behavior (playing video games) and each ad came either in a 'God version' or a standard version. Here are the two versions of the skydiving ad (both versions had a picture of a person skydiving):
Amazing Skydiving! God knows what you are missing! Find skydiving near you. Click here, feel the thrill!
Amazing Skydiving! You don't know what you are missing! Find skydiving near you. Click here, feel the thrill!
The percentage of users who clicked on the skydiving ad in the ‘God version' was twice as high as in the group which saw the standard "You don't know what you are missing" phrasing! One explanation for the significantly higher ad success rate is that "God knows…." might have struck the ad viewers as being rather unusual and piqued their curiosity. Instead of this being a reflection of increased propensity to take risks, perhaps the viewers just wanted to find out what was meant by "God knows…". However, the response to the bribery ad suggests that it isn't just mere curiosity. These are the two versions of the bribery ad (both versions had an image of two hands exchanging money):
Learn How to Bribe! God knows what you are missing! Learn how to bribe with little risk of getting caught!
Learn How to Bribe! You don't know what you are missing! Learn how to bribe with little risk of getting caught!
In this case, the ‘God version' cut down the percentage of clicks to less than half of the standard version. The researchers concluded that invoking the name of God prevented the users from wanting to find out more about bribery because they consciously or subconsciously associated bribery with being immoral and rejected by God. These findings are quite remarkable because they suggest that a a single mention of the word ‘God' in an ad can have opposite effects on two different types of risk-taking, the non-moral thrill of sky-diving versus the immoral risk of taking bribes.

Clicking on an ad for a potentially risky behavior is not quite the same as actually engaging in that behavior. This is why the researchers also conducted a separate study in which participants were asked to answer a set of questions after viewing certain colors. Participants could choose between Option 1 (a short 2 minute survey and receiving an additional 25 cents as a reward) or Option 2 (four minute survey, no additional financial incentive). The participants were also informed that Option 1 was more risky with the following label:
WARNING Eye Hazard: Option 1 not for individuals under 18. The bright colors in this task may damage the retina and cornea in the eyes. In extreme cases it can also cause macular degeneration.
In reality, neither of the two options was damaging to the eyes of the participants but the participants did not know this. This set-up allowed the researchers to assess the likelihood of the participants taking the risk of potentially injurious light exposure to their eyes. To test the impact of God reminders, the researchers assigned the participants to read one of two texts, both of which were adapted from Wikipedia, before deciding on Option 1 or Option 2:

Text used for participants in the control group:
"In 2006, the International Astronomers' Union passed a resolution outlining three conditions for an object to be called a planet. First, the object must orbit the sun; second, the object must be a sphere; and third, it must have cleared the neighborhood around its orbit. Pluto does not meet the third condition, and is thus not a planet."
  Text used for the participants in the ‘God reminder' group:
"God is often thought of as a supreme being. Theologians have described God as having many attributes, including omniscience (infinite knowledge), omnipotence (unlimited power), omnipresence (present everywhere), and omnibenevolence (perfect goodness). God has also been conceived as being incorporeal (immaterial), a personal being, and the "greatest conceivable existent."
As hypothesized by the researchers, a significantly higher proportion of participants chose the supposedly harmful Option 1 in the ‘God reminder' group (96%) than in the control group (84%). Reading a single paragraph about God's attributes was apparently sufficient to lull more participants into the risk of exposing their eyes to potential harm. The overall high percentage of participants choosing Option 1 even in the control condition is probably due to the fact that it offered a greater financial reward (although it seems a bit odd that participants were willing to sell out their retinas for a quarter, but maybe they did not really take the risk very seriously).

A limitation of the study is that it does not provide any information on whether the impact of mentioning God was dependent on the religious beliefs of the participants. Do ‘God reminders' affect believers as well atheists and agnostics or do they only work in people who clearly identify with a religious tradition? Another limitation is that even though many of the observed differences between the ‘God condition' and the control conditions were statistically significant, the actual differences in numbers were less impressive. For example, in the sky-diving ad experiment, the click-through rate was about 0.03% in the standard ad and 0.06% in the ‘God condition'. This is a doubling but how meaningful is this doubling when the overall click rates are so low? Even the difference between the two groups who read the Wikipedia texts and chose Option 1 (96% vs. 84%) does not seem very impressive. However, one has to bear in mind that all of these interventions were very subtle – inserting a single mention of God into a social media ad or asking participants to read a single paragraph about God.

People who live in societies which are suffused with religion such as the United States or Pakistan are continuously reminded of God, whether they glance at their banknotes, turn on the TV or take a pledge of allegiance in school. If the mere mention of God in an ad can already sway some of us to increase our willingness to take risks, what impact does the continuous barrage of God mentions have on our overall risk-taking behavior? Despite its limitations, the work by Kupor and colleagues provides a fascinating new insight on the link between reminders of God and risk-taking behavior. By demonstrating the need to replace blanket statements regarding the relationship between God, religiosity and risk-taking with a more subtle distinction between moral and non-moral risky behaviors, the researchers are paving the way for fascinating future studies on how religion and mentions of God influence human behavior and decision-making.  

Reference: Kupor DM, Laurin L, Levav J. "Anticipating Divine Protection? Reminders of God Can Increase Nonmoral Risk TakingPsychological Science (2015) doi: 10.1177/0956797614563108   

Note: An earlier version of this article was first published on the 3Quarksdaily Blog. Kupor DM, Laurin K, & Levav J (2015). Anticipating Divine Protection? Reminders of God Can Increase Nonmoral Risk Taking. Psychological Science PMID: 25717040