Tag: hypothesis

Chance and Necessity

If we free-associate the word “chance” you may arrive at “I’ll take my chances” before potentially arriving at Thomas Bayes’ “Doctrine of Chances”. Jacques Monod was an early explorer of the collision of probability and chance in biology.

THE PRINCE OF CHANCE

Jacques Monod grew up just down the coast from Monte Carlo in Cannes, France, another town famous for its casinos and, later, its film festival. Graced with movie star looks—one prominent French journalist described him as a “prince” who resembled Hollywood icon Henry Fonda, as well as considerable musical talent, and an exceptional intellect, Monod struggled to decide on a career path through his twenties. After distinguishing himself in the French Resistance, Monod rose to fame not as an actor or musician, but as a brilliant biologist. He shared the 1965 Nobel Prize in Physiology or Medicine for seminal discoveries about how genes work.

A pioneer in the field of molecular biology, Monod was privy to the blizzard of discoveries in the 1950s and early 1960s about the molecules that determined the characteristics of living things—what Monod and others dubbed “the secrets of life.” He kept close company with a relatively small international community of leading researchers. For example, when James Watson and Francis Crick cracked the structure of DNA (deoxyribonucleic acid) in 1953, Monod was one of the first with whom Watson shared the breakthrough.

But as a Frenchman steeped in his culture’s deep philosophical traditions, Monod was interested in science for more than just science’s sake. After the war, Monod befriended France’s leading philosopher-writer Albert Camus, and the two men pondered questions of human existence in Left Bank cafés. Monod felt that the public misunderstood the principal purpose of science as being the creation of technology. Rather, Monod believed technology was merely a by-product. He said, “the most important results of science have been to change the relationship of man to the universe, or the way he sees himself in the universe”—a relationship of equally intense interest to his friend Camus.

Monod thought that there were profound philosophical implications of the new molecular biology, particularly in the realm of heredity, which had gone largely unnoted in the broader culture. Several years after his Nobel Prize and Camus’ untimely death, he decided to write a book to try to bring the meaning of modern biology to laypersons.

“[T]he ‘secret of life’…has been laid bare,” he wrote.

“This, a considerable event, ought certainly to make itself strongly felt in contemporary thinking.”

Monod used several chapters to describe the insights that had very recently emerged from the study of DNA and the deciphering of the genetic code. He understood this knowledge would be unfamiliar to most readers, so he included an appendix with chemical structures of proteins and nucleic acids, and a primer on how the genetic code worked.

In a matter-of-fact style, he explained genetic mutations as accidental alterations—substitutions, additions, deletions, or rearrangements—in the text of DNA, in the sequence of the long strings of chemical bases (ACTTGATAA, etc.) that make up genes.

Then, almost without warning, he turned to the broader implications of how mutations arise in DNA. It is worth quoting him at length for after 111 pages of background, he delivered one of the most powerful ideas in five centuries of science (all italics are original):

“We call these events accidental; we say they are random occurrences. And since they constitute the only possible source of modifications in the genetic text, itself the sole repository of the organism’s hereditary structure, it necessarily follows that chance alone is at the source of every innovation, of all creation in the biosphere.

“Pure chance, absolutely free but blind, at the very root of the stupendous edifice of evolution: this central concept of modern biology is no longer one among other possible or even conceivable hypotheses. It is today the sole conceivable hypothesis, the only one that squares with observed and tested fact. And nothing warrants the supposition—or the hope—that on this score our position is likely ever to be revised.

“There is no scientific concept, in any of the sciences, more destructive of anthropocentrism than this one.”

In essence, heretofore obscure discoveries in biochemistry and genetics (largely studied at that time in simple bacteria) had upended two millennia of philosophy and religion that put humans at the center or apex of creation. “Man was the product of an incalculable number of fortuitous events,” Monod wrote. “The result of a huge Monte Carlo game, where our number eventually did come out, when it might not well have appeared.”

Le Hasard et la nécessité (Chance and Necessity) appeared in France in October 1970. It was a fairly technical book with several chapters on philosophy and genetics, and those appendices full of chemical diagrams. A first-time author, Monod did not know what reactions to expect.

The merde hit the fan.

The book received dozens of reviews across France and quickly became a bestseller—second only to the French translation of Erich Segal’s Love Story (this was France after all. After it was translated into English, reviews and interviews with Monod were featured in several of the most prominent British and American newspapers and magazines.

Many commentators immediately recognized the threat chance posed to traditional ideas of humanity’s origins and purpose. To Arthur Peacocke, a British biochemist turned prominent theologian, Monod had put forth “one of the strongest and most influential attacks of the century on theism.” A flurry of articles and books appeared with titles such as Anti-Chance: A Reply to Monod’s Chance and Necessity, Beyond Chance and Necessity, and God, Chance, and Necessity. Monod was invited to debate philosophers and theologians both in France and abroad, on television, radio, and in print.

American Calvinist theologian and pastor R.C. Sproul summed up the high stakes posed by chance in the first page of his book Not A Chance:

“It is not necessary for chance to rule in order to supplant God. Indeed, chance requires little authority at all if it is to depose God; all it needs to do the job is to exist. The mere existence of chance is enough to rip God from his cosmic throne. Chance does not need to rule; it does not need to be sovereign. If it exists as a mere impotent, humble servant, it leaves God not only out of date, but out of a job.” More than two hundred pages later, Sproul concluded:

“Chance as a real force is a myth. It has no basis in reality and no place in scientific inquiry. For science and philosophy to continue to advance in knowledge, chance must be demythologized once and for all.”

Sproul and other critics argued that what scientists perceived as chance merely reflected a lack of knowledge of true causes. Perhaps that was the expression of hope to which Monod alluded—the hope that as scientists learned more, our position on the role of chance would somehow be revised.

A SECOND CHANCE

The ensuing fifty years have not played out as either Monod or his detractors hoped. The Frenchman thought that the new insights from molecular biology should be a turning point for modern society-away from traditional beliefs about causes in the natural world toward one that embraced randomness and our chance existence.

Ha! Fat chance. The excitement and fuss stirred by Chance and Necessity simmered down, and Monod passed away a few years later. Surveys reveal that the majority of Americans, for example, continue to believe that everything on earth happens for His reasons.

But Monod’s critics should take no comfort. The province of chance in the biosphere and human life has been revised, although not at all in the scope or direction that they hoped.

The domain of chance has expanded into realms neither Monod nor anyone else imagined.

As we have learned much more about the history and workings of the planet, we have been startled to discover how the course of life has been buffeted by a variety of cosmological and geological accidents—without which we would not be here. As we have explored human history, we have seen how pandemics, droughts, and other civilization-changing episodes have been triggered by random, singular events in nature that easily might not have happened. And as we have probed human biology and the factors that impact our individual lives, we have caught chance red-handed, reigning over the often-thin line between life and death.

This book tells the stories that Monod could not—of astonishing discoveries from the planetary to the molecular scale, from great upheavals across the globe to the machinery of chance that operates within every cell of every creature, including ourselves. And while these discoveries vaporize the comforts of anthropocentrism, the story of chance, I hope you will come to agree, is much more than highfalutin philosophy or the refutation of theologians’ wishful thinking.

I hope that you are awed—awed by the power and the drama of asteroids slamming into the planet, of continents colliding, and of the rapid rising and falling of ice and oceans; awed by the realization that we live on (and are at the mercy of a planet that is far more unstable than our short lives perceive; awed by the knowledge of how random chance is at the source of all of the beautiful and wondrous creatures with whom we share the planet; awed by the unique invisible accidents that made each one of us; and awed by the fact that we humans, recent descendants of bands of hunter-gatherers who persevered through a period of exceptional chaos, have in just the last fifty years or so, figured all of this out!

My goal here is to be comprehensible without being comprehensive. It is almost trivial to claim that the world is the way it is or that we are here because of a long chain of chance, albeit fortunate, events. The explanatory power I seek comes from specificity. It is essential to unpack some of those events to appreciate how they shape the direction of life. The layout of the book follows a simple three-part logic. I’ll begin with inanimate, external chance events that have shaped the conditions for life (Part One, “Stuff Happens”), and then turn to the internal random mechanism within every creature that generates the adaptations to those conditions (Part Two, “A World of Mistakes”). Then, I bring the story to the personal level (Part Three, “23 and You”) and how chance impacts our natural lives, as well as our deaths. Our chance-driven existence shatters long-held beliefs about humanity’s place and raises challenging questions about the meaning and purpose of our lives. In the Afterword, I’ll offer some possible replies with the help of some special guests.

This is a relatively small book for a really big idea. Science has given us a handful of really big ideas over the centuries, but they have been received in funny ways. Darwin had a huge idea that was very simple to understand, and even though the evidence is massive and everywhere, many refuse to believe it. Einstein had a brand new idea, and even though few understand it or the evidence for it, most everyone seems to believe it. Monod had a great idea, but these days most people (other than scholars) have not heard of it, or of him.

My greatest hope, then, is that this short book might be chance’s second chance.

Sean B. Carroll, A Series of Fortunate Events: Chance and the Making of the Planet, Life, and You, Princeton University Press, 2020, pp. 6-12.

Modern biology as described by Monod pushes the linkage of probability, randomness and chance to the center. At the time, this was a very radical and profound way of looking at biology. If we combine Monod’s biology with theoretical physics like Lawrence Krauss’ A Universe from Nothing: Why There Is Something Rather than Nothing, we realize that accidentality is the bedrock on which our knowledge of the universe is built.

Science-Watching: New Insights into Polyamorphism Could Influence How Drugs Are Formulated

[from the Royal Society of Chemistry’s Chemistry World, by Patrick de Jongh]

Results from a study combining experiments and simulations could overturn the assumption that amorphous forms of the same compound have the same molecular arrangement. The team behind the work claims to have prepared three amorphous forms of the diuretic drug hydrochlorothiazide and determined that they have distinct properties and distinct types of disorder. ‘If polyamorphism is proved in the future to be a universal—or at least not a very rare—phenomenon, then the pharmaceutical industry will need to make screens for polyamorphism and this will also be an opportunity for patenting,’ comments Inês Martins, from the University of Copenhagen in Denmark, who led the work with Thomas Rades.

Crystalline active pharmaceutical ingredients (APIs) often suffer from poor solubility. A common strategy to circumvent this problem is converting APIs into their amorphous form. This has been demonstrated for various APIs, including hydrochlorothiazide. However, the physical properties of polyamorphs are dependent on how they were prepared. Given there are no straightforward techniques to study how molecules interact and organise themselves in amorphous materials, the area is poorly understood.

Nevertheless, a team surrounding Rades and Martins set out to identify how amorphous forms of the same API, presenting different physicochemical properties, differ from each other. They decided to study hydrochlorothiazide as it was previously shown to have polyamorphs with glass transition temperatures above room temperature, which facilitates the preparation, isolation and analysis of its different polyamorphs. Starting from crystalline hydrochlorothiazide, they produced three polyamorphs: polyamorph I via spray-drying, polyamorph II via quench-cooling and polyamorph III by ball-milling. Thermal analysis revealed a significantly lower glass-transition temperature for polyamorph I (88.7°C), whereas polyamorphs II and III had similar glass-transition temperatures (117.5°C and 119.7°C, respectively). The polyamorphs also demonstrated very different shelf-life stabilities against crystallisation.

Subsequently, they studied polyamorphic interconversions by submitting the polyamorphs to the preparation conditions used for other polyamorphs. For example, polyamorph I (obtained by spray-drying) was subjected to quench–cooling or ball-milling. Identifying temperature as a critical parameter, they observed that polyamorph II could be obtained from polyamorphs I and III, but the reverse pathway was not possible. Meanwhile, they observed polyamorph I and polyamorph III interconvert. These results demonstrate polyamorph II is the most stable amorphous form.

Source: © Thomas Rades/University of Copenhagen
Researchers used a variety of techniques to elucidate the different polyamorphs that can be produced from crystalline hydrochlorothiazide and the polyamorphic interconversions that occur when a specific amorphous form is submitted to temperature or milling treatments

‘The problem out of the gate with polyamorphism as a concept is how to tell the difference between a well-defined metastable amorphous structure and an unrelaxed one that simply results from kinetically trapped defects introduced during processing. This is hard to define since the amorphous structure is statistical in any case,’ comments Simon Billinge, who studies the structure of disordered materials at Columbia University in the US. ‘They process the samples very differently. We know—from our own work—that this results in amorphous phases with very different stabilities against recrystallisation, for example, but is this polyamorphism? On the other hand, they find that the pair distribution functions of each of their “forms” are identical. There is no experimental evidence for a distinct structure. Taken together, the results do little to advance my understanding of polyamorphism.’

Distinct dihedral angle distributions

To get further information on how the polyamorphs are different on a molecular level, Martins and Rades turned to molecular dynamics simulations, comparing the dihedral angles around the sulfonamide groups in polyamorphs I and II. ‘Polyamorph I, which has a large number of the molecules with a dihedral angle similar to the one reported for crystalline hydrochlorothiazide, has a lower physical stability and faster structural relaxation time than polyamorph II, which has a broader dihedral angle distribution. Our findings indicate that a broader dihedral angle distribution seems to contribute to a better physical stability and slower structural relaxation,’ says Martins. They therefore hypothesise that having half the molecules with a conformation closer to crystalline hydrochlorothiazide and half of the molecules with a different conformation could help in establishing specific molecular arrangements that would favour the stability of the amorphous form.

The team also says the simulations corroborated its experimental results that polyamorph I can transform into polyamorph II, while the opposite conversion did not take place.

However, Billinge does not believe the computational studies provide conclusive evidence: ‘There is a detailed molecular dynamics analysis where different annealing conditions in the simulations give some slightly different statistics on the molecular conformations, but despite their claim, the resulting computed pair distribution functions do not look like the measured ones, so we have no way of knowing if the molecular dynamics is capturing what is happening in the real material. For amorphous materials, it is very difficult to equilibrate them in a molecular dynamics simulation, so you will be looking at artefacts of how the ensemble was created. Any claims to have found polyamorphism from molecular dynamics simulations by themselves are therefore questionable.’

Rades says their results can change the field of pharmaceutics: ‘We expect that other drug molecules may exhibit polyamorphism and the question would be which structural parameters would be different. In the case of hydrochlorothiazide, the dihedral angle distribution was found to be a parameter contributing for the formation of different polyamorphs. In other drugs, maybe the dihedral angle distribution (molecular conformations) could be different as well, but also maybe the type of intermolecular interactions can play a more important role in the formation of polyamorphs.’

The team now hope the pharmaceutical industry will look at amorphous systems differently and not assume that all amorphous forms of the same compound are the same. ‘Knowing this and considering that a certain polyamorph will have better physical stability, solubility or dissolution properties than another polyamorph, this will be an opportunity for the pharmaceutical industry to prepare tablets of a drug where the dose could be lower than tablets containing the crystalline form,’ concludes Rades.