The beginnings of life: Chemistry’s grand question

Posted on November 19, 2014 by


Scientific American; b August 1, 2012 — Charles Darwin was a chemist. Granted, he made no notable contributions to chemistry. But in a 1871 letter to his friend Joseph Hooker he had the following to say:

“It is often said that all the conditions for the first production of a living organism are now present, which could ever have been present. But if (and oh! what a big if!) we could conceive in some warm little pond, with all sorts of ammonia and phosphoric salts, light, heat, electricity etc. present, that a proteine (sic) compound was chemically formed ready to undergo still more complex changes, at the present day such matter would be instantly absorbed, which would not have been the case before living creatures were found.”

In imagining a “warm little pond with ammonia and phosphoric salts” Darwin was squarely placing the origin of life in the realm of chemistry. It was clear to him that his theory of natural selection was crafted to explain what happens after life had gotten off to a start. Organisms after all were made of molecules; that much was known even then. Friedrich Wöhler’s pioneering synthesis of urea from inorganic substances in 1828 had dealt a blow to vitalism and demonstrated that the precursors of life are simple chemicals. In fact Darwin was more influential than he ever imagined; biomolecules like RNA undergo their own natural selection based on fidelity of replication, and while this molecular-level variation and duplication certainly operated on the early planet, today this kind of deliberate selection  – known as “directed evolution” – is used to discover everything from new antibodies against cancer to more efficient enzymes for making biofuels.

Yet even though Darwin seemed to appreciate it, most of the public does not clearly recognize the origin of life as a quintessentially chemical conundrum. In fact it’s chemistry’s grand question, just like the Big Bang is physics’s, evolution is biology’s and consciousness is neuroscience’s. The origin of life is a question as pregnant with grandeur and almost mystic significance as the origin of species and the origin of the universe. Yet more needs to be done to remind the public that chemistry, the same chemistry that explains the structure of nylon and helps us make detergents and drugs, also proudly sports the origin of life as its big question. Far too many people think of the origin of life as a biological problem. But Darwin clearly realized the boundary between chemistry and biology, and so should we.

Soupists and smokers

Stanley Miller who kicked off modern origin of life research as a problem in organic chemistry (Image: Universe Review)

Stanley Miller who kicked off modern origin of life research as a problem in organic chemistry (Image: Universe Review)

More than eighty years after Darwin speculated on his little pond, Stanley Miller took up the thread of life’s chemical origins. Standing on the shoulders of Alexander Oparin and J B S Haldane who had pondered the problem, Miller performed a now classic experiment in which he simulated a simple reducing prebiotic atmosphere consisting of ammonia, methane and nitrogen and water in a reaction vessel. A spark through this combustible mix that simulated lightning revealed the presence of amino acids – some of life’s key building blocks. Miller again demonstrated that the origin of life is a question of organic chemistry. Since then many variations on the basic Miller version have been implemented and each has produced one or the other of the crucial chemical components of life, namely amino acids, nucleic acids, sugars and lipids. Each of these has succumbed to creative schemes demonstrating their prebiotic synthesis from simple, plausible molecules like cyanide, formaldehyde and carbon monoxide. The latest salvo in the fray was by John Sutherland from Manchester who in 2009 demonstrated the most plausible synthesis of ribonucleotides – the components of RNA – from basic chemical precursors; this suddenly breathed new life into what is commonly regarded as the most consistent and likely scenario for life’s origins – the RNA world. It is sometimes said that the origin of life is a question so remote and multifactorial that we may never find out how it all actually happened no matter how many “what if” scenarios we conjure up. Yet simple chemistry has revealed rational likelihoods for almost every puzzle – from RNA synthesis to the handedness of amino acids – that has been posed. It’s also chemistry that has been at the heart of many other alternative theories of life’s origins, from Alexander Cairns-Smith’s “life from clay” idea to the various proposals dealing with the extraterrestrial seeding of earth by organic compounds.

While Miller and his fellow “soupists” blazed the initial paths in origins of life research, a startling new era dawned in the 80s with the discovery of potential life-sustaining factories in the most unlikely environments. The finding that life thrives in deep hydrothermal vents opened a whole new chapter in the field, again avowedly chemical. Black smoker chimneys located miles beneath the ocean have for millions of years been orchestrating a tumultuous union of hot, metal-rich, acidic chemicals arising from volcanic vents with cool alkaline waters. The unholy meeting of these two chemical opposites leads to a violent precipitation of minerals including the silicate mineral olivine, one of the most ubiquitous components of our planet’s rocky landscape. The precipitation of these minerals results in chimney like structures that can be miles high. The convecting thermal currents in these chimneys provide an abundant source of life’s sine qua non – energy. The metals can act as catalysts for simple reactions which involve sulfur, carbon monoxide and water. In recent years, because of the sheer energy hidden inside them, their capacity to catalyze key reactions like the Krebs cycle and concentrate reactants and products in microscopic pores and the uncanny resemblance of some of the iron and sulfur compounds to crucial iron-sulfur cores found in proteins, these mighty smokers have been considered by many scientists to precede or at least accompany the origin of life on the surface. Prominent among the “smokers” are scientists like Nick Lane and the patent attorney Günter Wächterhäuser who moonlights in the field as a “hobby”. These theories provide the “metabolism first” counterpart to the “replication first” camp. Together they may account for both genetic inheritance and chemical metabolism.

Having said this, it’s clear that we still have a very long way to go. Nobody knows how a mixture of amino acids, sugars, lipids and nucleotides forms proteins, enzymes and functional DNA and RNA, let alone makes the momentous leap into achieving a self-containing, replicating and metabolizing reaction system. Yet if the origin of life is chemistry’s great question, chemistry also provides a tool of singular importance for understanding it – self-assembly. Self-assembly is a phenomenon that’s ubiquitous in our world. It’s involved in everything from DNA replication and the mechanism of detergent action to the formation of crystals and the buildup of misfolded protein in Alzheimer’s disease. Self-assembly in its various guises has already been recognized by a Nobel Prize and there is no doubt that its practitioners will be lining up for more recognition in the future.

The bond that both shakes and stirs

Deep sea hydrothermal vents can be a fertile source of both simple biological chemicals as well as energy (Image: Consortium for Ocean Leadership)

Deep sea hydrothermal vents can be a fertile source of both simple biological chemicals as well as energy (Image: Consortium for Ocean Leadership)

The essence of molecular interactions is the chemical bond and these come in a variety of shapes and sizes, usually depending on the degree of sharing of electrons. The most important bonds that we know are the covalent bonds that link carbon atoms to each other and to other elements. Although covalent bonds are an indivisible part of chemistry and biology, the signature of self-assembly is what’s called non-covalent interactions. Covalent bonds are strong, but what’s key for understanding biological chemistry are weak bonds. Biology is one domain where weak is not just good but essential. Examples of weak bonds include Van der Waals forces (that allow us to liquefy gases for instance) and most importantly, hydrogen bonds. Hydrogen bonds arise when a hydrogen atom bonded to an electronegative element like nitrogen or oxygen feels an electrostatic tug from another electronegative element. This leads to the hydrogen being partially shared between the two atoms (the exact description is more nuanced). Hydrogen bonds which were postulated by Linus Pauling as being key to biology are what enable DNA to be a double helix and contribute to the exquisite three-dimensional shape of proteins. It’s simple; without hydrogen bonds there would be no life. The beauty of these bonds is that they are strong enough to maintain structure and hold molecules in an appropriate shape but weak enough to quickly break and reform when needed. This “on demand” property leads to hydrogen bonds being essential players in the most important biological processes, including the translation of RNA into protein, the catalytic reactions of enzymes and the action of neurotransmitters and hormones. Without hydrogen bonds DNA would not replicate, enzymes would not catalyze, proteins would not fold. Life would not have stood a chance.

Even when there were no proteins or nucleic acids, hydrogen bonds must have been paramount in life’s origins. Covalent bond formation itself is often helped by hydrogen bonds that serve to guide the reacting molecules into the proper orientation. But more importantly, this amazing molecular glue is crucial for the life-giving properties of the most common and enigmatic substance on the planet- water. The wholly unique properties of water that allow it to sustain life arise from the ability of each water molecule to form a maximum of four hydrogen bonds to other water molecules. This geometric arrangement immediately leads to many of water’s signature qualities, like its unusually high heat capacity and its ability to dissolve a variety of molecular shapes and sizes in its expansive hydrogen bonded network. This cage-like network is also what allows water to crucially form low-density ice that floats on the surface of water bodies, insulating and protecting the life forms beneath. There is no doubt; hydrogen bonds have turned water into life’s matrix. And since all the important chemistry during life’s origins would have occurred in water, it would have been impossible without these interactions.

Grease is good

The hydrogen bonds in water make possible its unique properties, including the cage like structure of ice (Image: Concepts in Biochemistry)

The hydrogen bonds in water make possible its unique properties, including the cage like structure of ice (Image: Concepts in Biochemistry)

For a long time origins of life research focused mainly on amino acids and nucleotides since after all they are the building blocks of proteins, DNA and RNA. Left on the sidelines were the ugly cousins of these key components – fatty acids and lipids. But contrary to today’s medical wisdom, when it comes to life’s origins grease is good. Grease in the form of simple fatty acids was responsible for one of the defining events in the ascent of life; the formation of cell membranes and vesicles. Fatty acids belong to a group of molecules called amphipathic compounds. As the name indicates, these compounds have two ends, a “water-loving” or hydrophilic end and a “water-hating” or hydrophobic end. As almost any schoolchild knows, oil and water don’t mix. What most schoolchildren don’t appreciate is the supremacy of this principle in the origin of life. When mixed together in water, amphipathic molecules cluster their hydrophobic ends together and form structures like bilayers and vesicles. For would-be molecular contenders, vesicles can provide a molecular version of a clean room, a literal bubble that’s exquisitely shielded from the rigors of early earth including heat, water and radiation. Fragile molecules that are otherwise being ruthlessly buffeted by the elements suddenly find a safe haven for self-assembly inside these vesicles. Vesicles were almost certainly key during the formative years of molecular assembly because of their ability to sequester other molecules and allow them to experiment with metabolism and replication at leisure. Nucleotides, ions, amino acids and sugars could enter these vesicles and indulge in chemistry that would have been impossible in the turbulent exterior. Recent experiments including pioneering work by the Harvard biochemist Jack Szostak have shown how vesicles could replicate themselves and in turn serve as chambers for RNA synthesis. Various mechanisms including shearing by rocks have been invoked to support vesicle budding, assembly and replication. These observations have put the early role of fatty acids in orchestrating essential biochemical reactions on a firmer footing.

A mechanism for the growth, budding and assembly of vesicles (Image: Szostak lab, Mass General)

A mechanism for the growth, budding and assembly of vesicles (Image: Szostak lab, Mass General)

The effect that contributes to this behavior of fatty acids and vesicles is a fundamental chemical principle called the hydrophobic effect. While the operation of the hydrophobic effect is apparent in the separation of oil and water, the exact explanation of the hydrophobic effect is a matter of continuing and endlessly fascinating research. Entropy certainly plays an important role in mediating this effect. When an oil molecule contacts water, the water molecules who detest the presence of this greasy intruder have no choice but to reform a cage-like structure around the oil molecule. This leads to them being more ordered, and in a loose sense more order implies low entropy, a generally unfavorable state of affairs. Now when another oil molecule is introduced into this environment, water is more than happy to let these two hydrophobes contact each other so that it’s freed up from the space between them. This leads to more disordered water molecules and more entropy which translates into a happy situation for both molecular species. The real explanation of the hydrophobic effect is more complicated but the entropy driven self-assembly of hydrophobic molecules captures the essence of the effect, and since these are fundamental principles derived from basic thermodynamics, there is no doubt they were operational during the origin of life.

The origin of life is a problem in chemistry

It’s worth noting that self-assembly, hydrogen bonds and the hydrophobic effect are all essentially chemical principles. Some of them gather support from quantum mechanics and thermodynamics, fields traditionally rooted in physics. But reducing these molecular-level effects to atomic-level explanations does not help us understand how they contributed to life’s origins. With respect to physics these effects are decidedly emergent. They can be best applied to an understanding of life at their own level and on their own terms. Understanding the qualitative properties and rough strengths of hydrogen bonds helps me understand their key role in the DNA double helix much more than any accurate quantum mechanical calculation of their origin ever could. Understanding the hydrophobic effect is much more about a hodgepodge of sometimes loosely defined yet entirely scientific and eminently useful concepts like polarity, entropy and molecular shape and size than it is about the precise atomic origins of water-oil repulsion. Physics is too atomistic in addressing origins and biology is too emergent. Chemistry addresses the problem at the right level. And this is what makes the origin of life chemistry’s big question.