The flutter of a butterfly…

The butterfly effect is a common trope in popular science and fiction that attempts to convey a hard-to-grasp scientific fact: a very small change in the initial conditions can create a significantly different outcome. The phrase refers to the idea that a butterfly's wings might create tiny changes in the atmosphere that may ultimately alter the path of tornado a large distance away. 

A small twist of fate can alter a lot for one person but I have always suspected the impact of  one event on the course of the entire world. Can one person, one event, one random turn, truly alter the course of history? Aren't we all just pieces in one gigantic puzzle linked together in a million tiny ways but unable to influence the picture as a whole. But then, once in a while, I encounter examples where one person does manage to alter the entire course of history - unintentionally perhaps, but irreversibly altered nevertheless. 

In many ways, the story below - laced with irony, rebellion, intrigue and love - symbolizes the Economist's law of unintended consequences. Ever since I first heard the story, I have been trying to reconcile the monumental impact of this one man, Gavrillo Princip and this one chance event on the world as it exists today. The thing that caught my attention in this story was not the action of men because they failed in their own ways. But it was the role of chance, randomness or luck that truly stood out for me. 

Gavrillo Princip (1894-1918), was a Bosnian Serb who was responsible for the assassination of Prince Archduke Ferdinand, heir to the throne of Austria-Hungary and his wife, Sophie, Duchess of Hohenburg. Princip was born in a family of serfs at a time when Serbia was in a tumultuous state of transition. 

In 1878, under the Treaty of Berlin, Austria-Hungary received the mandate to occupy and administer the Bosnia while the Ottoman empire retained official sovereignty. As part of the same treaty, Serbia was accorded the status of a sovereign state which soon transformed into a kingdom under Prince Obrenovic who ruled within the borders set by the treaty. However, this peaceful state of existence changed when as part of a military coup, the king and the queen of Serbia were violently murdered and Peter I was installed as the new king. This new dynasty was friendlier to Russia than to Austria-Hungary and over the next decade, disputes erupted as Serbia moved to reclaim its former fourteenth century empire. Serbia's military successes in these campaigns further emboldened the nationalistic elements in Serbia and the serbs in Austria-Hungary who were irked by the Austro-Hungarian rule. 

As a christian serb (serf) family living in northwestern Bosnia, the Princips (and other serbs) were often oppressed by their muslim landlords and forced to live off the little land they owned. This led to large scale discontent against the Austro-Hungrian empire. At the age of 13, Princip's brother moved him to Sarajevo and this gave him more opportunities for protest. In 1911, Princip joined the Young Bosnia, a society that wanted to separate Bosnia from Austria-Hungary and to unite it with the rising kingdom of Serbia. The following year, Princip was expelled from school for being involved in demonstrations against the Austro-Hungarian authorities. Coincidentally, after the Balkan wars in 1912-1913 the Austro-Hungarian administration in Bosnia and Herzegovina became extremely serbophobic and declared a state of emergency as the governor closed many schools and Serb societies and inflamed the historic anti-serb rhetoric. All this further fueled the young Princip and he left Sarajevo to arrive in Belgrade. He then volunteered to join Serbian Guerrilla bands fighting under the leadership of Major Vojin Tankosic, who was a member of the Black Hand - the leading terrorist organization in Serbia at the time. Three young men, including Gavrillo Princip at the age of 19, were thus trained, armed and tasked with the assassination of Prince archduke Ferdinand of Austria-Hungary by Major Tankosic. These young men were a product of their times as they sought freedom from the Austro-Hungarain empire to unite with the serbs, in hope of a better future. 

Gavrillo Princip, PC: Wikipedia 

Franz Ferdinand's life too is a charming story in itself. He was born in Austria to the younger brother of the emperor Franz Joseph, Archduke Karl Ludwig and was thus not the direct heir to the throne. However, in 1889, his cousin, Crown Prince Rudolf committed suicide and this left emperor Franz Joseph's younger brother (and Franz Ferdinand's father) next in line to the throne. When his father, Archduke Karl Ludwig, died of typhoid fever in 1896, Franz Ferdinand became the prince and heir to the throne. 

            
Archduke Franz Ferdinand, PC: Wikipedia    Duchess Sophie, PC: Wikipedia 

As a young man, Franz Ferdinand had met Countess Sophie Chotek at a ball in Prague but was forbidden to marry her as she was not a member of one of the reigning dynasties of Europe. Sophie and Prince Franz stayed in touch through letters and their relationship blossomed, away from the eyes of the court. Deeply in love, Franz Ferdinand refused to marry anyone else and after numerous appeals from him and his royal friends (Tsar Nicholas II of Russia, German emperor Wilhelm II and Pope Leo XIII all appealed his case), emperor Franz Joseph finally permitted the prince to marry Sophie. He however imposed a condition that the marriage would be morganatic and that their children would have no succession rights to the throne. Sophie was further forbidden from sharing her husband's rank, title, precedence or privileges and could normally not appear in public with him. Despite these brutal restrictions, the two married in 1900 and stayed together for the rest of the lives (and even deaths).  

In 1913, in the midst of the crisis in Serbia, Emperor Franz Joseph commanded the archduke to observe military maneuvers that were scheduled for June 1914 in Bosnia.  June was also a time of great unrest in Serbia as it commemorates the 1389 Battle of Kosovo against the Ottomans when the Sultan was assassinated by a Serb. This was a time for serbian patriotism and military observances. Although, Duchess Sophie could never share the archduke's rank and splendors as the prince; she would not let him travel alone as she feared for his safety amidst all this turmoil. In fact, if you were to believe historian AJP Taylor, love was the reason they met their deaths on this fateful day in June - "[Sophie] could never share Franz Ferdinand's] rank… could never share his splendors, could never even sit by his side on any public occasion. There was one loophole… his wife could enjoy the recognition of his rank when he was acting in a military capacity. Hence, he decided in 1914, to inspect the army in Bosnia. There at its capital Sarajevo, the Archduke and his wife could ride in an open carriage side by side…Thus, for love, did the Archduke go to his death".

On the fateful morning of June 28, 1914, The Archduke and his wife arrived in Sarajevo by train and the entire motorcade including the governor of Sarajevo began its journey as per a pre-announced program. Six armed assassins including Princip were positioned along the motorcade route with a single target in mind - Austria's heir apparent, Archduke Franz Ferdinand. 

The first two assassins along the route failed to act but the third assassin, Nedeljko Cabrinovic, who was armed with a bomb decided to take action. He threw his bomb on the motorcade but unfortunately the bomb bounced off the convertible and exploded under the next car in the motorcade. This blast caused a major furore as 16-20 people were wounded. The assassin Cabrinovic swallowed his cyanide pill and jumped into the nearby river to evade the police. Unfortunately for him though, the river was running dry and only 6 inches deep and the cyanide pill did not quite work.  He was thus taken into custody and severely beaten. A disaster seemed to have been averted as the assassination attempt appeared to have been foiled. The motorcade sped away to arrive at the town hall for the scheduled reception where the Archduke (understandably) complained about the reception accorded to him - "Mr. Mayor, I come here on a visit and I get bombs thrown at me. It is outrageous." After a few soothing words from Sophie, he finally thanked the people of Sarajevo for their ovations "as I see in them an expression of their joy at the failure of the attempt at assassination." 

After the commotion of the explosion and the rally, Franz Ferdinand and Sophie gave up their planned program and decided to visit the wounded from the bombing at the nearby hospital. The remaining assassins had all dispersed to avoid capture and it seemed that the  plot was indeed foiled. 

Now, this is where fate makes an unlikely entry and alters the course of events. 

Once the Archduke and Duchess board the motorcade, the accompanying general orders that the royal car be  taken to the Hospital through a route that avoids the city center. However, the driver of this motorcade, Leopold Lojka did not get the order and took a wrong turn into the Franz Josef street which had a cafe. Fortuitously enough, after the failed assassination attempt, Gavrillo Princip had wandered to a nearby food shop - Schiller's Delicatessen on the same street. As the universe conspired, it was at this point that the Archduke's motorcade made the wrong turn. The driver, upon being told about the changed route was trying to reverse the car when the engine stalled and the gears locked giving Princip an unexpected opportunity. Taking the chance, Princip stepped forward and fired two shots from a distance of about 5 feet. The first bullet wounded the Archduke in the jugular and the second inflicted an abdominal wound on the Duchess (who some reports say was pregnant at this time). Both victims remained seated upright but died while being driven to the Governor's residence for medical treatment. As reported by Count Harrach who was with the motorcade, Franz Ferdinand's last words were "Sophie, Sophie! Don't die! Live for our children!" followed by six or seven utterances of "It's nothing" in response to questions about his pain. 



Princip and the other assassins were meanwhile caught and imprisoned for high treason. At his sentencing, Princip stated that his second shot was aimed at Governor Potiorek than the Duchess. Princip was 19 years old at the time of the assassinations and was thus too young to receive the death penalty. In fact, he was 27 days short of his twentieth birthday which would have made him eligible for death penalty under the Habsburg law. Instead, he received the maximum sentence of twenty years in prison where he contracted tuberculosis and died on 28 April 1918. Princip had stated under cross-examination: "I am a yugoslav nationalist and I believe in unification of all South Slavs in whatever form of state and that it be free of Austria." Princip, was a young terrorist who wished for nothing but the betterment of his people. 

Assassination illustrated in the Italian newspaper Domenica del Corriere, 12 July 1914 by Achille Beltrame. 

As fate conspired, this single event - the assassination of the Archduke, triggered a chain of events that resulted in the first world war within a month. Austria-Hungary blamed Serbia and dragged Germany into the war. Russia responded and France got involved leading finally to the entry of Great Britain. The war began one month after this assassination and continued for 4 years leading to one of the bloodiest wars in world history that spanned almost the entire world in one way or another. The first world war, of course, was directly responsible for the Second world war which ultimately shaped the world as it exists today. And so, one can extrapolate that the gun shot that was intended to start a local protest by killing the Archduke actually triggered a whole lot more than that. 

Ironically, Princip was saved from the death sentence by his young age but he only lived long enough to witness the horrors of the first world war and the millions of deaths that directly resulted from his actions. I cannot be certain but I am fairly sure that given the benefit of hindsight and knowing the consequences of his actions, Princip might have chosen to not fire his gun on that fateful day. Because if you extend the chains of causation - the current middle east crisis, the Israel-Palentinian conflict, the cold war, Hiroshima and Nagasaki, Pearl Harbor, The third Reich, the treaty of Versailles, the first world war - they all occur at the other end of that one gunshot! 

I have long suspected the impact of individual agency on the course of world history because it often seems that our actions are often drowned by those of the multitudes around us, especially when it comes to changing the world. And yet, when I come across examples like this, I am forced to believe in the agency of one - for better or for worse. The agency of one, aided by the randomness and chaos that drives us is sometimes just as powerful as the flap of that butterfly's wings. 

Post-Script: 
My journey into understanding the first world war began through a podcast (Hardcore History by Dan Carlin) but it soon led me to dig deeper in books by John Keegan (The First World War) and Barbara Tuchman (The guns of August). This story has particularly captured my fascination even as I have dug-deeper and read more about it in wikipedia and other media outlets. 

Reference Sources: 
1) http://en.wikipedia.org/wiki/Archduke_Franz_Ferdinand_of_Austria
2) G. J. Meyer (2007). A world undone: The story of the great war, Bantam Dell.
3) John Keegan (2000). The First World War.

4) http://en.wikipedia.org/wiki/Assassination_of_Archduke_Franz_Ferdinand_of_Austria
5) http://en.wikipedia.org/wiki/Gavrilo_Princip
6) http://www.firstworldwar.com/bio/princip.htm
7) http://www.theguardian.com/world/2014/jun/27/gavrilo-princip-sarajevo-divided-archduke-franz-ferdinand-assassination
8) http://www.theguardian.com/world/2014/jun/27/guardian-1914-analysis-archduke-franz-ferdinand-shooting

From being comatose to completing a marathon - all in a day! That's what happens when a python eats...

Eating a meal after a week-long starvation might be enough to make any meal seem hearty; but when a burmese python eats after starving for up to a whole year, the 'heartiness' quotient of the meal is raised to an entirely different level as the python's heart 'literally' grows by up to 40% after feeding. And, this is only one of many, quirky facts that can make the giant, scaly, unmoving, coiled hulk of a python seem interesting. 

Unlike the many snake species that actively forage and hunt for their prey, the pythons (and some others like boas, vipers and pit-vipers) employ a sit-and-wait tactic for hunting. Although this saves them the energy costs of active hunting, it also limits their feeding opportunities and imposes additional adaptations as their body has to adapt to large intervals (up to a year for a burmese python) between meals. These meals, though rare, are not small by any means - a python is capable of consuming anywhere from 80-150% of its own body weight in one meal! That's like a 100 lb. person eating anywhere from 80-150 lb. of food in one sitting. These dietary extremes have resulted in unique physiological adaptations. 

As a python lies in wait for its next meal, it enters a stage of quiescence and down-regulates both the structure and function of its gut. At the risk of damaging its own lining in the absence of food, the stomach stops producing any acid. The pancreas and the gall bladder stop their secretions and the intestinal epithelium (which normally absorbs the nutrients from a meal) atrophies. The proteins that transport nutrients across the gut lining are also shut down. In fact, in addition to the gut, other organs of a starving python such as the liver, heart, pancreas and the kidneys are also dramatically shrunk  and inactive during starvation.

But things change dramatically with that one meal. 

When a cavalier prey passes by an inert python, it is often unprepared for the viciousness of the attack and the crushing defeat that are to follow. The python lunges on its prey, impaling it with its teeth and then gradually crushing it to death by coiling around it. The muscular hulk of the python coils and crushes its thoracic cavity suffocating it to death. Once the prey is dead, then begins the slow process of swallowing it, usually head-first. The python uses its paired set of pterygoid teeth (on the palate) in alternating steps and literally walks over the prey's skull internalizing it in the process. Considering the enormous sizes of a python meal, its skull is extremely flexible and mobile with multi-hinged jaw joints and a flexible ligament between the lower jaws. The process of swallowing a large prey is further aided by the axial muscles (lining the body wall) that gently propel the food - first into the expandable esophagus and then into the waiting stomach.

Although fascinating in itself, the ingestion of the prey is only the beginning of the wondrous world of a python's alimentary canal. The prey begins to putrefy naturally soon after ingestion and generates large amounts of gas (that luckily we don't have to smell) and this further increases the girth of the python. Before you conceive of an exploding python, let me clarify that this build-up of gases is not enough to cause an explosion but it does cause severe compression and exert additional pressure on the internal organs. It also interferes with ventilation and blood flow (much more than how one might feel after two thanksgiving meals). Thus, the python needs to digest the large and intact prey before it starts decaying significantly and the only tool at its disposal is a dormant gut with no secretions. 

A Burmese python swallowing a laboratory rat which it had killed by constriction. (B) A Burmese python 24 h after consuming a rat meal greater than 50% of the snakeʼs body mass. This snake had experienced further distension of its body after feeding due to the build up of gases within the ingested dead rat.

Unlike most mammals including us, the starving python does not have baseline acid levels in its stomach. Remarkably though, within a day of the meal, the quiescent gastric lining is rapidly re-activated and it starts pumping massive amounts of H+ and Cl- ions into the stomach lumen dropping its pH from being neutral 7 at rest to extremely acidic (at pH 2) within almost 24 hours of the meal.

The post-feeding profile of gastric pH for Burmese pythons demonstrating the rapid drop in pH after feeding, the steadymaintenance of a very acidic pH during digestion, and the rise in pH upon the completion of gastric digestion when acid production ceases.
The stomach also releases an inactive protease enzyme, pepsinogen, which gets activated under the acidic conditions. The cleaved and now functional pepsinogen acts on the prey to dissolve the soft tissues and skeletal elements. By the third day, only 25% of the ingested meal (which could be as big as a kangaroo) remains within the stomach and it largely consists of the difficult-to-digest parts such as  the trunk-vertebrae, the hind limbs, tail and hair. By about 6 days, the prey is almost completely dissolved and all that remains is a mat of hair to be sent on its way out. 

                                              

                                          

Daily X-ray images of a python digesting a rat that was equal to 25% of the snakeʼs body mass. At 1 day post-feeding (DPF), the ratʼs skeleton is completely intact within the pythonʼs stomach, whereas by day 6 the ratʼs skeleton has been completely broken down and passed into the small intestine.

As the stomach acids and enzymes work, small amounts of the digested food are metered into the intestine by the opening and closing of the pyloric sphincter - a valve between the stomach and the intestine. On entering the intestine, the acidic pH of the stomach chyme is neutralized by the alkaline environment and the pH increases to 6.5 within a few centimeters. Other enzymes from the bile such as the amylases, lipase's and proteases from the pancreas also join the party as the food is broken down to its elements in the intestine. 

Once the food has been digested, the next step is the absorption of the broken-down nutrients - normally done by the tiny finger-like projections (called villi) in the intestinal wall. The python's intestine and the villi, however, are completely shriveled during the starvation period to conserve energy. However, within a few hours of the feeding (while the prey is still intact in the stomach) the dormant intestine is woken up to a flurry of activity - all in anticipation of the nutrients that will be coming in. The intestine doubles the length of the villi, up regulates the amino acid uptake rates and the activity of its enzymes.  In fact, within 24 hours of the feeding, the mass of the intestine increases by up to 70%. 

                            

Images of the small intestine of similar-sized Burmese pythons fasted and at 2 and 10 days post-feeding (DPF). By 2 DPF, the intestine has increased in diameter due primarily to hypertrophy of the epithelial cells; a response that has reversed by 10 DPF.

                       

Transmission electron micrographs illustrating the rapid post-feeding lengthening of the pythonʼs intestinal microvilli, reaching a peak in length at 3 days post-feeding. After digestion is complete (after day 6), the microvilli shorten in length and return to dormancy. Bar in images represent 1 μm or one thousandth of a millimeter.

In keeping with the increased flurry of metabolic activity, there is also an increase in the size of most, if not all, internal organs of a python - the liver, the kidneys, the heart and the pancreas. In fact, in order to keep up with the increased need for energy, nutrient transport and organ growth, the python heart grows in mass by 40% within 48 - 72 hours of a large meal. 

                              

Wet mass of the heart, pancreas, liver and kidneys plotted against time post-feeding for Burmese pythons fasted (0) and following the consumption of rodent meals equal to 25% of the snakeʼs body mass. Feeding generates respective increases in wet mass of 40%, 94%, 106% and 72% for the heart, pancreas, liver and kidneys.

The growth of an organ can be achieved by two means - by either an increase in the number of cells that make up the organ (hyperplasia) or by an increase in the size of individual cells (hypertrophy). The growth is a python heart after a meal appears to be hypertrophic or driven by increase in cell size than number. In fact, studies show that a growing python heart up-regulates a system of genes akin to what happens when we augment our cardiac output - either due to pregnancy or with exercise. These events are rather different from the pathological program that is activated by hypertension, heart attacks etc. The quirky physiology of a python heart thus becomes an interesting subject to study even from the perspective of human health and disease. 

                  

                                      

The increase in the size of a python heart post-feeding is characterized by cellular hypertrophy. Compare the heart size of a starving python and that at 3 days post-feeding (DPF) Scale bar, 2 mm.

Two days after feeding, after absorption of the nutrients, the unabsorbed material (largely hair) begins to enter the large intestine. With each continuing day of digestion, the cecum and the large intestine fill with unabsorbed waste material, that is ultimately expunged as a bolus along with urate. Within a week after the meal, the last of the prey exits the stomach and the small intestine and these organs  begin the shut-down process anew. Within ten days, the stomach pH rises, the enzyme activity drops down and the intestinal mass declines. The other organs too begin to shrink to their former state.

The question that remains though is what regulates this system level change in the organ size and function. 

Studies suggest the involvement of two pathways - hormonal (systemic effect of hormones) and luminal (arising from the gut lumen itself) in mediating these rapid changes in organ size and function. The levels of many hormones that regulate gut function such as neurotensin, glucagon, insulin and cholecystokinin increase sharply after a meal. Experiments where small segments of the gut were surgically isolated from the rest of the gut but kept connected to the circulation were also able to increase their function upon a meal suggesting that a link to the blood circulation was sufficient to drive these systemwide changes. The gut lumen itself was also seen to play a role in triggering the initial responses as direct injection of nutrients (amino acids and proteins) into the python's small intestine was able to reawaken the intestine from dormancy. Interestingly though, injecting saline, glucose or lipids did not have the same effect on the python's intestine. 

The factors underlying the increased heart size are however much less clear. In order to study the possible involvement of systemic factors on cardiac output, scientists injected blood plasma from fed and starving pythons into mice. Much to their surprise, components in the plasma of a fed python had similar effects on the heart of a starving python and of a mouse and caused significant increase in their respective heart sizes. 

                               

Fatty acids in the blood of a fed python induced cardiac growth in a starving python. Infusing fasted pythons with fed plasma or a mixture of the three individual fatty acids resulted in increased heart mass (heart weight/body weight) thus mimicking the effect of a meal (3 DPF). Bovine serum albumin (BSA) was used to solubilize FAs and is therefore used as control here to show that it alone did not have the safe effect as the fatty acids.

                                                              
Seven-day infusion of the same three fatty acids in mice also resulted in increased heart growth (as measured by the size of the ventricle).

Interestingly, the fed-python-plasma continued to function in a starving python even after treatment with heat and a protease - suggesting that the active ingredient was likely not a protein. Scientists then suspected the involvement of lipids (since they are resistant to heat and proteases) since feeding led to sharp increases in the levels of lipids and fatty acids in the python blood (see the turbid opaqueness of python plasma after feeding). Careful studies identified three commonly known lipids - myristic, palimitic and palmitoleic acid to be responsible. Injecting these three lipids in the precise ratio to a starving python over a 7 day period resulted in significant growth in the heart - comparable to what would have been triggered by a good meal. Strangely however, the effect of these lipids was limited to the heart as the other organs - liver or muscle showed no change. Supplementing these lipids individually also had no effect. 

                           

Levels of non-esterified fatty acid (NEFA) and triacylglyceride (TAG) concentrations in the blood plasma are significantly increased after feeding (see the milky opaqueness of the plasma at day 1 - 2 after feeding).

Careful observation also shows that the levels of the lipids shoot up in the plasma even before the digestion has begun in earnest (see peaks at days 1 and 2 and compare with the X-rays of the prey from earlier). This suggests that the lipids are not coming from the digestion of the prey but are indeed a signal produced by the python to synchronize its various organ systems and to prepare them for the upcoming phase of hyperactivity. 

Also of interest is the fact that despite such high levels of lipids in its blood (to the extent that the plasma appears cloudy), the python heart shows no lipid deposition. This again would be rather useful to many of us who worry about inching closer to a heart attack with every blob of butter or every additional french fry. If only, our hearts would be more like a python's and not deposit the fat around its vessels - we could eat everything that we wanted and yet avoid the consequences (or at least some of them).  

Despite the creepy-crawlies that I had previously associated with a python, now, it is a fascinating creature with some extremely cool biology. Imagine someone emerging from a near comatose state only to successfully complete a marathon! That is the equivalent of what a python does every time it eats a meal. 

References:

1) Cecilia A. Riquelme et al. Cardiac Growth Fatty Acids Identified in the Burmese Python Promote Beneficial cardiac growth in Science 334, 528 (2011)

2) Digestive physiology of the Burmese python: broad regulation of integrated performance
by Stephen M. Secor The Journal of Experimental Biology 211, 3767-3774 in 2008