Saturday, January 8, 2011

The Failing Hypothesis

On the hypothesis that the failing heart is energy starved: lessons learned from the metabolism of ATP and creatine.

Abstract

Adenosine triphosphate (ATP) and phosphocreatine fall in the failing heart. New insights into the control of ATP synthesis, supply, and utilization, and how this changes in the failing heart, have emerged. In this article, we address four questions: 

What are the mechanisms explaining loss of ATP and creatine from the failing heart? What are the consequences of these changes? Can metabolism be manipulated to restore a normal ATP supply? Does increasing energy supply have physiologic consequences (ie, does it lead to improved contractile performance)? In part 1 we focus on ATP, in part 2 on creatine, and in part 3 on the relationship between creatine and purine metabolism and purine nucleotide signaling.

Internet humor

The Internet has long been a resource for the circulation of humorous ideas and jokes. Countless web-sites are devoted to the collection of Internet humor, and every day e-mail crosses the world, containing the text of humorous articles, or jokes about current events.

"Internet humor" is distinguishable from "Humor on the Internet" through the concept of ownership. There are definite examples of humor restricted by copyright law on the internet; examples include the cartoons of Dilbert or the newspaper columns of Dave Barry. "Internet humor" is regarded as that which belongs to the public domain.

Internet humor may also be regarded as humor that specifically relies on characteristics belonging to the Internet, such as the domain name slurls or the "geek" or "hacker" humor (i.e., humor that would not exist if not for the Internet), some of which can be considered ironic.

Generally, this type of semi-institutionalized humor starts as a specific group's in-joke, and grows until it reaches a significant portion of Internet users, gaining popularity, "rules" and mythos.

The concept of authorship with regard to Internet humor is very difficult to define. Frequently a "list" type joke may get started but within a few generations of distribution it evolves beyond recognition. A classic example is the well-known "you have two cows" joke — after circulating in other media throughout the 1980s, it seems to have first appeared on the Internet in 1993 with simple descriptions of communism, capitalism, and socialism. However, it was later expanded to include all forms of government, regional variations, philosophical systems, and even art movements. Attempting to define an "author" of the joke hence becomes impossible, and it becomes a publicly owned resource, simply because no one could validly claim legitimate ownership.

Though the Internet has allowed the global explosion of collectively-authored comedy, its precursors existed on bulletin boards, corporate messaging systems, and even through such low-tech mechanisms as the facsimile since at least the 1970s.

Interrogating Nature - to reveal God's way?

Long gone, I trust, are the days when the work of the mediaeval schoolmen could be dismissed. Men like Aquinas, who tried to integrate Aristotle with Augustine, were clearly persons of the highest talent. That they were working on material now by many discredited does not take away from the strength of their minds or their processes of thought. 

They worked on what they had. It does, though, show us what power there was in church thinking and also in the intense experience of faith. It was such an experience that brought Aquinas to silence in the last few months of his life, after a vision that convinced him of the reality of faith more than all his reasoning had done. And the overlapping of the two systems - Christianity and science - illustrates how slowly institutions guarding the levers of knowledge allow themselves to be displaced or even modified. Christianity itself carried within it pagan acts and polytheistic and classical practices that were even carried over into the New Testament.

The Royal Society Charter said it was devoted 'to the glory of God the Creator and the advantage of the human race ...'. Yet the Fellows were forbidden to meddle 'with divine metaphysics and morals'. Nor were politics allowed. But all the key players in science around that time - Copernicus, Galileo, Kepler, Descartes and Newton - understood what was at stake in the revolution they were engineering. This was the place and fate of the soul. Newton's proof that all space obeyed the same laws abolished the essential separate and different space kept by Aristotle and Augustine and Aquinas for God and the soul. Where now could God and the soul actually exist? Therefore, what place did God and His Faith have in the new philosophy, the new knowledge?

From the beginning, the Royal Society insisted that Nature must be studied closely, since it is God's other book, alongside Scripture, as their tutelary figure, Francis Bacon, had said. And they believed the best way to make sense of this book of Nature was by conducting many different, instrumentally directed, observations and experiments on it. Put Nature to the question. Interrogate it, said Bacon the lawyer.

The Civil War had taught men such as John Wilkins and Robert Boyle that public religious controversy led to conflict, and the aim of the Royal Society, as its first historian Thomas Spratt put it in 1667, was to show 'an unusual sight to the English nation, that men of disagreeing parties and ways of life have forgotten to hate, and have met in the unanimous advancement of the same works'.

These were the early men of observational and experimental science, yet Robert Boyle, in the late seventeenth century, one of the geniuses of the group, whose Law - Boyle's Law - proved early on that the Society could do Big Science, published at enormous length on the intimate relation between admiration of the works of God and the great advantages experimental philosophy would bring to religious faith and vice versa.

Joseph Priestley, another Fellow, in the late eighteenth century saw a direct link between the right religion (in his case Dissenting Protestantism) and the right kind of natural knowledge. He used his chemical and electrical experiments to promote his dissenting views about the character of divinity. In the twentieth century, Arthur Eddington, another Fellow, was clear about the basic unity of his own spirituality as a Quaker and the principles of modern physics. He argued that mystical religious experience and modern physical science were consistent and indeed supported each other, as he made clear in public lectures.

Others were more careful in their public statements. Newton was the most significant example. He was worried about the public reaction to his unorthodox religious views, which were very close to a Unitarianism that would have had him cast out of Cambridge, so he kept quiet about them. Some of his closest allies, like William Whiston and Samuel Clarke, got into terrible public trouble by expressing these views. Newton saw God as the direct cause of gravity. 

And he said of space that it was 'as it were, God's sensorium' - seeing space as the realm of divine ideas. Finally, Michael Faraday, similarly cautious, was a Sandemanian, and that rigorous sect's views informed his science and that of many other eminent Fellows of the Royal Society. Non-Brits, especially the French, were always puzzled by the religious component in the thinking of British scientists, often the greatest British scientists through the centuries. Even Darwin was sure that his account of speciation with natural selection as one of its engines was not logically connected with atheism.

Indeed, Simon Schaffer, the eminent Cambridge historian of the Philosophy of Science, has developed this. He sees three techniques characteristic of the Royal Society Project: a social technique (work together, witness together, trade together); a material technique (use instruments and machines, dissect, experiment, analyse); and a literary technique (describe these trials and observations in so much detail that the descriptions can be followed by all readers and trusted by them).

Interrogating Nature

There's a fair claim that the Royal Society saw its first shoots just over the road from the Sheldonian Theatre, in the gardens of Wadham College in the 1650s. The young Warden of Wadham, Dr Wilkins, had written a paper called 'How One Might Fly to the Moon'. And he was no mean politician. A Cromwellian through marriage, he attracted young Royalists to his college and later nipped over from Cromwell to Charles II without any recorded angst.
 
Wilkins encouraged a group of like-minded young gentlemen to take on the new philosophy of the observation and testing of Nature, as distinguished from theory alone. To inquire. To experiment. To interrogate Nature.

One thing that did come from Wadham, as well as the men who went on to London formally to start the Society, was the idea of a collegiate group: the notion of sharing ideas and of working as a group, and of commenting on and examining each other's ideas. This was key to the Society.

When Christopher Wren and the others moved to London to greet the new king, the group congregated around Gresham College. This had been founded by an Elizabethan philanthropist. It became a unique mix of high learning and public availability: the prototype of the Open University. At Gresham College, seven handsomely subsidised professors gave academic lectures that could be attended by anybody at all. That too became one of the guiding principles of the Society: that knowledge was free, open and available to all.

These men looked back to the great Elizabethan lawyer, courtier and essayist, Francis Bacon. He famously declared that 'knowledge is power' and he saw two books in the world, Nature and the Scriptures. To get knowledge from Nature it had to be questioned in the court of the mind; 'tortured' was another word he used. And that knowledge would reveal God's way and add to the relief of Man's estate.

The Royal Society was not the first of its kind. In the immediate past, there was the Academy of the Lynxes, formed in Rome in 1603, led by Frederico Cesi, to which Galileo belonged. Then there was the Academy of Experiment formed in Florence in 1567 by the Medici princes. One can trace these organisations back through the courts of the Caliphs in the early mediaeval Arab world, to the Academy of Plato in Athens. In all cases, these groups of inquirers had been small in number. Most had been in immediate contact with their patrons. Then there was the Parisian Royal Academy of Science, officially to be commissioned to discharge projects in the interests of the Crown.

The Royal Society was not like any of these. It was there 'for the Promoting of physico-mathematico experimental learning'. And 'Nullius in verba' was its motto. 'Take no man's word.' Experimenting was believing. Its open collectivity, its focus on experimental demonstrations, its assurance that these trials would reveal the works of God, its sense that economic and commercial projects are part of the divine plan and its literary determination to describe these trials and observations in such a way that they can be followed by all readers and trusted by them, makes it unique. Above all, it was independent. Crucial then as today. The monarch never attended its meetings.

One thing that strikes me about all these groups and many other key influential intellectual groups in science, art and philosophy, is how small was their membership. In our age of mass education it seems almost against Nature that so few so often accomplished so much. Is there something in smallness itself, as the man claimed, that is not only beautiful but, on significant occasions, uniquely effective? It has happened rather often. In fifth-century BC Athens, in the Florence of Michelangelo and Leonardo, in Shakespeare's London, the Edinburgh Enlightenment, in mid twentieth-century Cambridge, in the music of the Big Five in late-nineteenth-century Russia. Is something given to a small clique of brilliant and disputatious contemporaries to dig deeper?

The fact that we are in Oxford, famous in the Latin-speaking Christian world in the thirteenth century for its own small group of philosophers like Duns Scotus and William of Occam, brings me to a core subject in this observational history: that it charts the movement over centuries from one great dominating system in Europe and its colonies - Christianity - to what appears to be its great successor - science.