Better angels of our nature are closer than we thought...

Spontaneous giving and calculated greed - Wouldn't the world be a better place if that were true - but apparently it is!! 

For a long time now, man was considered to be just another animal with strong instincts for self-preservation. This made pro-social and altruistic behavior a puzzle for evolutionary biologists to solve. Why would evolution select for self-destructive behavior and how would that propagate? It is a fascinating question from an evolutionary perspective and people are still looking for the right answer/s. Many theories such as group selection, kin selection, social living, reciprocal altruism etc have been proposed over the years to explain the pro-social streak in our character. It has long been implicitly understood that human beings are inherently selfish creatures programmed by evolution for self-preservation. The better angels of our nature were thus considered to have evolved as an adaptation for social living (reciprocal altruism) and as an indirect way to preserving one's gene pool (group selection, kin selection)

However while cooperation is deemed central to human social behavior and requires individuals to incur a personal loss to benefit others, the underlying cognitive process was never really analyzed. Are people predisposed to selfishness, behaving cooperatively only through active self control; or are people inherently cooperative with reflection and prospective reasoning favoring "rational self-interest" ? Think about the question ! 

To me, this is a fascinating question and intuitively, I had almost always understood that it is rational thought that keeps our instinct for self preservation and selfish nature at bay. But like many things in science, this was a surprise too ! 

A recent report in Nature addresses this very question in a laboratory set up. They try and differentiate between our intuitive impulses and our reasoning abilities and their respective influences on our behavior.

Intuition is characterized by quicker, effortless, more automatic responses, made without insight into the decision process and with a strong emotional influence. Reflection on the contrary is associated with serial processing, effortful thought and rejection of emotional influence. Intuitive responses are also faster while the reflective responses take a while as multiple facets need to weighed and deliberated upon. This group has used time as a metric to distinguish between our natural impulses and our reflective responses. 

In their experiment, they use a monetary index to measure the participants' pro-social tendencies. If you share more money - you are letting the better angels of your nature guide you and thus exhibiting cooperative/ prosocial behavior.

As part of their "game", 212 subjects were recruited using the online labor market Amazon Mechanical Turk (AMT) which the authors consider is providing a reliable, more diverse subject pool than the usual pool of college undergraduates who are Western, Educated, Industrialized, Rich, and Democratic, or ‘WEIRD’ and a biased representation in themselves... ;) As part of the experiment which was conducted in groups of 4, each subject was given a finite amount of cash (US $0.40) and they were asked to contribute an amount of their choice to a common pool. Any money contributed to the common pool was doubled and split evenly among the four members of the group.  Rationally, it is more profitable for people to hold onto their money (0.40$ vs 0.80/5$ not knowing whether everyone will cooperate or not). Finally, the authors compared the decision times and the endowments made. They found that faster half of the decisions donated more money than the slower, more deliberated decisions (see below). They also found a linear relationship between the time taken and the amount donated. Quite intriguing to my mind but it is a correlation and doesn't suggest causality.

    

                            

Now to test for causality, they again recruited around 680 subjects on the AMT as earlier and experimentally manipulated their decision times in their one shot Public Goods Game (PGG) as earlier. The subjects were put under a time constraint and were thus pressured to arrive at their decision quickly (within 10s). The decisions here are thus forced to be intuitive than reflective. Also, a "time delay" set up for the second group was also established where subjects were encouraged to weigh their options and were forced to wait for at least 10s before making a contribution. This is expected to drive reflection and careful reasoning. Consistent with the previous observation, they find that subjects forced to make an intuitive decision tend to contribute significantly more money to the group than the subjects in the time delay condition. 

                          

I particularly like their priming experiment wherein they recruited 343 more subjects and conceptually primed them for intuition or reflection. One group was primed to trust their intuition more when they were asked to write a paragraph about a situation in which their intuition led them in the right direction while careful reasoning has led them down the wrong path. The other group, primed for reasoning, was prompted to recall a situation in which intuition had led them the wrong way while careful reasoning had taken them in the right direction. And consistent with their findings till this point, the contributions to the pool were higher when people were primed to trust their intuition relative to the reflective process (see below). 

                          

This of course brings us back to the question which is one of the most difficult to answer in Science : Why?

Why are people intuitively predisposed to cooperation? The authors propose that people develop their intuitions in the context of everyday life where cooperation is typically advantageous since it is usually reciprocated and also because one's reputation is influenced by them. Further, since everyone grows up with the burden of social sanctions for one's actions and so we all develop cooperative and pro-social intuitions. And thus we need reflection to overcome this impulse and to adapt to situations which are not inherently advantageous to us (as in this experiment). The authors then try to test this hypothesis based on the assumption that greater familiarity with the laboratory cooperation experiments would attenuate these effects. They repeat their experiment of conceptual priming on a group of naive and experienced AMT subjects. Although I am not very convinced by this logic of theirs, I do appreciate the fact that they tried to test this theory. They do find that promoting intuition only increased cooperation in the subjects who were naive to the experiment. I would have liked to have seen this experiment in the pressured, time constraint set up because intuition, by definition is not something you can be trained for (so quickly at least!). And I would have liked to see, if the returning subjects perform differently when pressured for time. 

The authors further state that the subjects will only be intuitively cooperative if in their daily-life setting cooperation is advantageous. And thus cooperation will only be favored if there are enough number of similarly cooperative people. And this to me is a lot more understandable but it does need rigorous tesing. It is often seen that in resource-poor nations, people are not very cooperative when it comes to limiting resources like money, space, food, etc because there are not enough people to reinforce a pro-social tendency with reciprocity. This, thus leads to a vicious cycle of hoarding and accumulation which widens the gulf between the 'haves' and the 'have-nots'.

Based on their results the authors conclude that cooperation is culturally transmitted and is a product of social learning during development although it is tempting to conclude that 'cooperation' is innate or genetically hard-wired into us.

To my mind, what would also be interesting is to study the intuitive and reflective responses of people from different economies and different social backgrounds. The intuitive responses of children who are as yet uninfluenced by social mores would also be very revealing. But these, of course, remain questions for future studies.

And while the authors in this paper have explored the cognitive underpinnings of cooperation and pro-social tendencies in humans, there are a lot of questions that still remain to be addressed. To me however, this was a very interesting question with an equally interesting answer... 

In fact, this paper reminded me of Malcolm Gladwell's book titled "Blink". In the book, Gladwell, taps into examples and anecdotes from science, medicine, advertising, sales etc to establish an idea that spontaneous decisions, made in the blink of an eye, can often be as good - and sometimes even better than - carefully deliberated ones. He proposes that our mental processes and our adaptive unconscious have evolved to work rapidly and automatically from relatively little information.

Thus, on a superficial level, it seems that our intuitive decisions are in our best interest and that of others.  

I guess, even science is now telling us to live in the moment and go with our gut (microbiota or not)... ;) 

 

 To read more : 

1) Spontaneous giving and calculated greed : Nature, 489, 427–430 (20 September 2012)

2) Blink : the power of thinking without thinking by Malcolm gladwell

The creative destruction of medicine - are we ready for it yet ?

Imagine a world where you can monitor your blood glucose level 'live' every time you turn on your iphone.
Imagine being able to just scan a mole on your iphone and using an App to find out if it is cancerous or pre-cancerous.
Imagine having a portable angiogram built into your phone so that all you have to do is place it near your chest and wait for two more minutes.
Imagine being able to monitor the quality and duration of your sleep every night through your smart phone.

Does it all sound far and distant and a remote possibility to you... 

Well, Think again ! This is the present! :)

This was the message that was screaming from the slides of a recent presentation I heard which was titled - "The creative destruction of medicine". It was a fascinating talk by a great orator - Eric Topol on how the digital revolution will create better health care for us all. 

What I took away from the talk was this sense of hurtling towards a future where every aspect of our well being would be digitally monitored and controlled. And I know that doesn't sound very welcoming from how I said it - but to my mind this is an alarming trend. Not in the least because I am against technology or against computers - I love all the gadgets that have come along and made almost everything accessible at the press of a button or rather at the touch of a screen; but I do not like the way technology has invaded into the human space and is constantly nudging out the human influence from every sphere of life.  It is also distressing to think of all the complications that can possibly arise and that have not really been considered by people in their hurry to promote and adopt technology.

Some of these, are great applications and probably have great potential to reduce medical costs and to widen the influence and reach of quality health care but there are many questions here which need to be addressed carefully and I am worried that the technology 'cloud' is growing much too fast to let everything else catch up with it.

There are already examples of e-consultation, e-supervision, e-care in many hospitals where they have a centralized unit that is constantly monitoring the ICU and its patients through cameras, videophones etc. An example of this I came across recently was from the New Yorker piece by Atul Gawande about the 'Tele-ICU' set up in the Steward health-care system which was testing out this model of intensive care. As part of this telemedicine model, a centralized ICU command center was set up involving banks of computer screens that carried a live feed of cardiac monitor readings, radiology imaging scans, and laboratory results from the ICU patients throughout the Steward's hospitals. Softwares and codes monitored the results and produced yellow and red alerts when they detected patterns that raised concerns. Doctors and nurses manned the consoles where they could turn on high-definition video cameras and zoom into any ICU room and talk directly to the staff or the patients. With a total staff strength of 4, this set up was able to actively monitor and support the ICUs across ten remote hospitals. And with this perspective, when one thinks of the quote from an Indian entrepreneur in the Silicon Valley that medicine needs more software codes than doctors - one can almost understand....

"But" and this is a big glitch for me : technology and computers are invading our lives much faster than we are preparing for them. Imagine the issues that can possibly arise :

- Imagine a time when everyone would be able to access their vital stats and symptoms through their smart phone and have all the necessary tools for diagnosis from google. It would potentially make us all self-diagnosing hypochondriacs (or cyberchondriacs as Dr Topol likes to call them). Are we prepared for computers tracking and telling us about every breath we take or every heart beat of ours? Are we prepared to trust the internet for solving all our problems all the time? Because, as wonderful as this mass sharing of information is - it does leave plenty of room for wrong information to seep through. No one is really keeping track of the accuracy of all information available on the web. And if people lose track of this reality - problems will be less than a "touch-screen" away.

- Imagine issues with privacy... People hack into your accounts, steal your phone or your computer and they can find everything about you including your physical and mental status, disease risks, threats and allergies. People hack into public databases, monitor your search history and they will have access to all the weaponry they need to influence you. What happens when people use health risk to discriminate for employment, insurance, friendship or for that matter anything else. A lot of this is already happening is proving to be a challenge to the regulators!

- Insurance firms already discriminating for pre-existing conditions - how long would it take for risk and lifestyle factors to be factored into the equation... ? Would my risk for diabetes or heart attack (based on genetics, sequencing or family history) justify their over-charging me from adolescence or even adulthood?   

- Another interesting facet that emerged from the question answer sessions with Dr Eric Topol is the regulation  of these apps and technologies. I was surprised to know that some of these apps like the one for screening moles is not regulated or FDA approved. It sure maybe a great piece of work and rather accurate but if there are no checks and balances, anything and everything can find its way to the masses and that would be sure shot recipe for disaster. But the regulatory authorities and the control bodies are not yet effective and fully aware of the possible threat of these tools. How do you limit the access of technologies available on the web without being labeled a moral watchdog? Does an approval in one country automatically mean an approval for all others? Does an App or a software that work for caucasians work equally effectively for all other races - after all there are genetic, social and cultural differences among people.... How do you control the spread of the internet without being prejudiced or biased or dictatorial? Apple is already attempting and is fairly successful at establishing a monopoly of sorts in the field with its devices and its Apps. How do you thwart such issues of intellectual property vs public welfare ?

- And then consider the possible impact of genome sequencing. The costs of sequencing an individual's genome have come down so much that it can be afforded by normal people like you and me and the decline is an ongoing process. From being a decade long exercise that it was when it was done the first time, small hospitals can now sequence an entire genome in a matter of hours. Sequencing is being routinely used to shift our understanding of medicine from the perspective of a community to that of an individual - to test drug resistance, effectivity indices, susceptibility to diseases, infections, to diagnose, to give prognosis etc. And there have been some wonderful developments with this tool like the diagnosis of a little boy who suffered from a life threatening disease that couldn't be diagnosed till his genome was sequenced.

But what about risk factors, susceptibility indices and predictions ? Where do these predictions end and where does life itself begin ? We all know that a lot of times statistics are just numbers and more often than not, they are only a guideline for us. They cannot be treated as absolute truths in any way, shape or form. And more importantly, we are far away from a comprehensive understanding of the individual contributions of genes, mutations, variations, SNPs and lifestyle to the development of a disease.

- Another big concern of mine is the loss of human skill and involvement as machines take over. Every new generation of physicians and nurses is more and more dependent on technology and instrumentation. What happens when technology lets you down ? I am not referring to a take over of the world by corrupt robots and self-replicating computers but imagine the situation when it is only a simple power failure. In a world dictated by instruments even that will be debilitating. Will the next generation of doctors and nurses be able to use a stethescope to measure the heart beat and detect any abnormalities or would they be completely dependent on an ultrasound and a cardiogram ? Will they be able to measure the other vitals without their usual fancy gear ? Would they be able to perform a successful surgery without a robotic arm and a pinhole camera guiding them?

People in the developed countries are already losing their ability to carry out simple mathematics - addition, subtraction, multiplication and division - the argument being - "why tax the brain when there are calculators an arms-reach away?". People are unable to type correctly without a spell check and despite the ease of editing and typing, language is becoming more and more abbreviated. A lot of these are the unintended consequences of technology and one must consider them every time we let technology a step closer into our life. I, myself, realized these implications only after the massive power outage in San Diego in september last year. Coming from India, power cuts were a part of our life  - there would be one almost every day and we have lived with them. But seeing the effect of that one experience on the American populace made me thank my stars for the training. People here were in a state of panic as they abandoned vehicles on the street. There was panic everywhere as nothing from gas stations to grocery stores was functioning without the checkout counters.

- Another aspect of such technology dominated care that occurred to me was the increasing gap between the western world and the developing countries. While the west is battling with high-nutrition and stress induced diseases, the rest of the world is fighting infectious diseases, microbes, pathogens, malnutrition and poverty. The developing world is generating newer and more potent strains of flu and influenza, antibiotic resistant bacteria. The developed world on the other hand is pouring money to make the already comfortable lives of its people even more easy - leading to an increased incidence of diseases of the affluent - like obesity, diabetes, hypertension etc. But the problem here is that in a world that constantly shrinking, diseases do not remain quarantined - they spread faster than the news of them. The developed nations of the world have a selfish interest in preventing the development and spread of these resistant strains of bacteria and new strains of virus. But instead, they are working on reducing human skill, judgement and influence. To me, it doesn't seem like a wise approach.

- Lastly and perhaps most importantly, we are social creatures. We respond better to words of support and encouragement, a few moments of happiness than to the anti-depressants and prozacs. We need individual and social contact to thrive and flourish. And presently computers are replacing society out of our mainframe. As we spend more and more time on facebook hooked to our iPads and iPhones, we are becoming more and more "I" centric and losing track of the fact that we live in a society and that people are important. 

Everyone who knows science is aware of the reality that while every step forward in science gives us a few answers, it raises many more questions. Be it the baffling example of HIV resistant cohorts of women or the twins with different afflictions and behaviors. The human body is a complex machine and we as yet, do not have a complete understanding of all the parts and their interactions. Without such a clear picture, powerful technology would only release the power of decision making to an unaware and inexperienced public which will end up making important decisions about consulting or not consulting a doctor, ignoring or not ignoring a lesion without full awareness of the consequences.

At this point, while I am marveling the growth of technology and its impact, I am worried about its influence and about where it is leading us.
I wish and hope that people would think about the full consequences of their words and actions before they pick one side or the other and advocate. I am only reminded of the childhood story of the Arab and his camel in the desert.  We should be careful about how much we let something big into our life....

More reading:

1) Eric Topol's tough prescription for improving medicine 
2) Big Med By Atul Gawande in the New Yorker
3) One in a billion : A boy's life, a medical mystery 

Bug-gers making you fat ?!

The human microbiome or the genome of microbiota closely associated with humans has been under the limelight for quite some time. It has long been known that the human body harbors many different microbes - inside and on the outside. The human skin, hair, mucosal linings, fluids, orifices all provide great environments for a number of bacteria to flourish. The most abundant of these are probably even the most studied are the microbes that dwell in the human gut. To just give you a perspective of the scale of this colonization - let us consider some numbers. It is estimated that the human body harbors thousands (500-1000 species in the gut alone) of bacterial species and that we may in fact be carrying more bacterial cells in us than our own. It is roughly estimated that there are atleast 10^14 bacterial cells while there may be only about 10^12 - 10^13 of our cells in that body that we strive to protect and maintain. 

To me this is a fascinating thought. 

Now the role of these microbes has long been speculated and never really understood. The primary reason being it is technically very challenging to breed animals in such extreme isolation and then to determine the composition of our microbiome.  Technically, we couldn't analyse bacteria that we couldn't grow in culture and despite all this research there are only a handful of bacterial species that we can grow in our labs. But then there came the sequencing revolution. And as genomes got sequenced in days and now hours with low costs and high efficiency, we could now finally identify the bacteria that colonize us. Today in the era of "omes", microbiome is yet another genome scale enterprise and unlike some of the others, it is giving us some startling revelations. 

The composition of our gut microbiome has been seen to play a role in a large variety of physiological phenomena from obesity, to diabetes, to nutrient absorption, to infection and immunology. While certain bacteria cause infections and chronic inflammation leading to diseases like cancer, most are commensals or actually symbionts as we now are realizing. Over the past few months, the scientific literature has been bombarded with studies that delineate the role of these gut microbes and their association with our health and disease. The clinical success of fecal transplants and their ease and efficiency, also strengthen the future potential of these studies. Because if some of the evidence is to be believed, a lot of our diseases can be remedied by simply altering the microbes in our gut. 

This post deals with one of the recent papers in this arena which shows that sub therapeutic antibiotics can alter the murine colonic microbiome and adiposity of laboratory mice. 

Published in the recent issue of Nature, this study does raise some interesting questions. 

This study deals with one of the oldest controversies arising from antibiotic use in animal husbandry. For almost half a century now, it has been widely seen and reported that sub-lethal (for the bacteria, of course) doses of commonly used antibiotics promoted the growth of farm animals. Vertebrates across the board - from mammals (goat, sheep, cows) to poultry (Chicken, turkey) exhibited upto 15% of growth and increased weight gain when administered with sub-therapeutic doses of antibacterial agents (penicillins, macrolides, tetracyclines, ionophores etc). Since this effect was not agent specific, and was not shown by anti-fungals or anti-virals, the underlying mechanism was not clear. Since, the doses were sub-lethal, it did not kill the gut flora and therefore do the obvious. 

On the other hand, this use of sub lethal doses had stirred up a lot of public anxiety and fear about the rise of resistant bacteria and their spread to humans. While there was not direct evidence for this, the fear was justified to some extent. Mechanisticaly, it has been speculated that these sub-therapeutic doses might suppress the growth of toxin producing microbes and the sub-clinical infections particularly in the post-weaning period, which might indirectly reduce the energy invested on gut tissue replacement and immune response. But this was again never really experimentally tested.

In the recent issue of Nature, Martin Blaser's group at the New York University school of medicine do just that in trying to answer this decades old question. 

They exposed young mice at weaning to sub-therapeutic doses of antibiotics like penicillin, vancomycin, penicillin plus vancomycin, chlorotetracycline (STAT mice) or no antibiotic (control) in their drinking water. Seven weeks later then found that while there was no overall difference in the weight or size of these two groups of mice, there was however a over difference in the fat content of the two groups. The STAT mice had significantly higher levels of fat accumulated in them though they weighed the same and consumed the same amount of feed. The STAT treated mice also showed no significant differences in their feed efficiency - weight gained per unit of food consumed. Careful studies showed that while the animals treated with STAT showed an early growth spurt, the actual changes in fat mass began to diverge between the two groups only by week 16-20. In order to understand the events leading upto this they then analyze the animals for the levels of the various hormones that regulate appetite or satiety like leptin, ghrelin, peptide YY etc and they find no significant differences. 

They then examined the microbiome of the two groups to determine if the sub-therapeutic antibiotic treatment is leading to these metabolic changes by affecting the GI tract microbiome. And interestingly, they find that while the STAT did not lead to substantial changes in the overall microbial census, it did however lead to alterations in the composition of the microbial population. They find that in the fecal and caecal samples, there is an increase in the proportion of firmicutes vs the bacteroidetes upon STAT treatment and they propose that this taxonomic alteration is making the gut more efficient at extracting energy from the diet. Now, to my mind, while there is a significant change in the composition of the gut microbial community (bacteroidetes/firmicutes), the extent of this change upon different antibiotic treatments does not appear to correlate very well with effect of each antibiotic on the weight gain itself. 

 

(As can be seen in these graphs, while Penicillin causes maximum increase in the body fat % it only causes modest (but significant) changes in the alterations of the gut microbiota (Bateroidetes/ firmicutes). Although I do realize that it is difficult to find perfect correlations in most biological phenomena, I would have liked to see better correlation between the two graphs.) 

This is based on previous work where ob/ob mice which are genetically prone to obesity were found to harbor an increased population of firmicutes. They further find that STAT treatment affected the expression of genes related to short chain fatty acid (SCFA) synthesis which play a central role in colonic metabolism. And while different antibiotics affected SCFA genes in different ways, the overall effect was conserved. They validate their hypothesis further by showing increased levels of these fatty acids in the caecal contents of STAT mice vs control by direct measurements. It is known that increased levels of these SCFAs can stimulate adipogenesis but absorption into the portal system. Thus, it appeared that while both groups of mice were taking in the same amount of calories, the STAT treated mice had an altered microbiome that was extracting more energy from the same input. Validating this hypothesis, the fecal pellets of the STAT mice indeed showed lesser caloric value. 

Now, the increased energy efficiency can be accounted for by multiple means: 

1) Increased absorption of SCFAs from the colonic epithelium

2) Increased production of SCFAs directly altering the colonic metabolism

2) Increase in the efficiency of storage and conversion of these SCFAs into adipocytes

The authors fail to test the first hypothesis even as they show by gene expression profiling that STAT induced intestinal changes result in substantial changes in the regulation of lipid, cholesterol and triglyceride metabolism in the liver. Upon examining the third possibility, the authors find that the adipose tissue in the STAT mice shows no substantial physiological difference compared to the controls in cell density, local inflammation, or metabolic potential. 

The authors thus postulate that the sub therapeutic antibiotic treatment somehow selected for an altered microbiota that was able to extract a higher proportion of calories from dietary complex carbohydrates that were relatively indigestible in the control mice. The resultant SCFAs from microbial activity could then enable enhanced lipogenesis by being absorbed and transported through the portal system. 

One thing that does not become clear to my mind is how and why the STAT treatment alters the microbial population. The authors propose that the STAT actually represents a compounded perturbation and thus has profound, long term alterations in the community state. But this does not give a selection pressure favoring the rise of firmicutes vs the bacteroidetes. 

A News and Views column in the same issue of nature by Harry J Flint from the University of Aberdeen raises some more interesting possibile explanations for the observed phenomena. Dr Flint proposes that antibiotic treatment may also affect the energy provision for the host - such as by altering the transit of food through the gut which is in turn known to affect SCFA absorption and fiber degradation. He hypothesizes that the microbial signals could differentially influence the muscles that control transit of food through the gut. He also raises the possibility that microbial populations (or their metabolic products) could alter early adipogenesis in the early stages of mammalian growth. Another innovative possibility suggested by Dr Flint is that the antibiotics might suppress bacterial in the small intestine (instead of in the colon where the paper tested) and thus make more digestible nutrients available for absorption in the small intestine. 

All these possibilities are all quite intriguing and theoretically plausible (though improbable to me) and one can only say that further experimentation is required for us to completely understand how sub-therapeutic doses of antibiotics affect animal health.