(Below is the article presented at the TFUSA meeting by Babar Mustafa. Babar Sahib has done a wonderful job of turning a complex and difficult subject into a simple and understandable reading. It explains how simple chemical reactions transform into complex biological structures and come alive. F. Sheikh)

Animation of Matter

How life originated, is one of the most fundamental questions and has preoccupied humanity throughout its existence. Every culture and religion has a creation myth. The true story began to unfold in a period of less than a hundred years around 1850s to 1950s, with the emergence of three great ideas in biology. Cell theory, Darwin’s theory of evolution by natural selection and the discovery of the structure of DNA, combine neatly to describe how life works. But they also bring us to the brink of cracking the big question itself: How life began.

It is only very recently, with our solid understanding of the genes, proteins and mechanics of these living chemical processes, that we can seriously question how they came to be in the first place. Modern biology has revealed that intricate networks of chemical reactions drive reproduction, inheritance, sensation, movement, thought, and all of the things that life does. None of this happens for free: energy is required to fuel these actions. The bottom line is that without energy, you are dead. It is here, in the microscopic and indeed atomic world of the cell, that we are finding the clues to understand these processes – the ones that keep you, your cells, and every cell alive, as they have for billions of years.

The invention of optical lens by a Dutch Linen merchant to check the density of fibers, followed by the work of dozens of men and hundreds of years of investigation into the stuff that life is made of, can be summarized in two line:

1). All life is made of cells.

2). Cells only arise by the division of other cells.

Before this discovery, life was considered to arise spontaneously, and this view, like a zombie still shambled along, lurching up again and again. The man who finally killed “spontaneous generation” dead was Louis Pasteur, in 1860 in France, when he showed with his experiments that without contamination microorganisms could not develop.  The implications of this theory were profound. It covers all life, a simple but comprehensive description of the innumerable inhabitants of the living earth. Diversity of life on earth is embedded in the magnificent range of different types of cells.

At about the same time, Charles Darwin in England was slowly and meticulously putting together an overwhelmingly compelling case that described how creatures evolve. Evolution, the idea that species are not unchangeable, was already being contemplated as a concept in the 19^th century but the process by which they changed (natural selection), was unknown.

Cell theory and natural selection are reflections of the same truth: Life is derived, begotten, not created. It’s incrementally and ultimately spectacularly modified, but, in essence, life is the adapted continuation of what came before.

A few thousand miles in east, Austrian holy man was planting a garden that would invigorate biology forevermore. Mendel was a monk but his legacy is of a scientific genius and world changing experimentalist. When Darwin was writing his masterpiece, Mendel had been studying pea plants and breeding them in tens of thousands. Large numbers make good statistics, what Mendel found in impressively large numbers was that, when crossing variants with one and another, the outcome in the offspring were entirely predictable. His experiments also resulted in determining that characteristics were inherited equally, one from each parent but that some of those characteristics were more equal than others. He bred tall plants with short ones and their offspring were always tall, rather than an average of the two heights. What followed was observation beyond that which is visible to the naked eye. New technologies of the twentieth century meant that the scale of biology was reducing from the organism to the cell, to the molecular and atomic level, and with this zooming in came the birth of modern genetics.

In 1953, Cambridge scientists Francis Crick and James Watson discovered the DNA double helix and the base pairing, they concluded the paper with one of science’s great understatement: “It has not escaped our notice that the specific pairing we have postulated, immediately suggests a copying mechanism for the genetic material”. By the 1960s, scientists knew that life was built of or by proteins, that proteins were built from amino acids, and that DNA was the hereditary matter that coded the proteins.

Descent with modification when traced backwards takes us to the Last Universal Common Ancestor (Luca). How did Luca originate is still the focus of research and the idea that a bolt of lightning and a primordial soup of chemicals kick started life is no longer a satisfactory explanation because now we know a lot more about the cells.

Louise Pasteur demonstrated that life does not emerge spontaneously, but life’s molecules do emerge spontaneously in the right environment. Molecules of life are not life yet itself, any more than a pile of bricks and lumber is a building.  At a minimum life is a metabolism, a network of chemical reactions that harvest energy and combines chemical elements into life’s molecular building blocks. Life also needs the ability to make more of itself – replicate- and pass its accomplishments to future generations. This does not mean that metabolism and replication must have appeared simultaneously.

I will try to share knowledge that brings us closer to a plausible answer to how these basic processes might have originated, may be separately, and finally got captured/organized inside a membrane forming a rudimentary cell.

Metabolism:

Metabolism can get going if its molecules are concentrated. Earlier speculations were like Darwin’s warm ponds, and then tidal pools were considered a variant of those ponds and now the hydrothermal vents on the pacific seafloor near the Galapagos Islands, are the top candidate as the laboratory where it all could start. Its raw materials come straight from Mother Earth herself, through searing hot fissures in the earth’s crust that overflow with nutrients, chemical energy, and the very catalysts that the warm little ponds lack. Hot water from these volcanic vents rises through chimneys abound in energy rich chemicals going through gradually decreasing temperature. Microbes have been found there using these chemicals and building their own organic molecules from energy rich inorganic molecules, as well as from vent’s abundant sources of carbon and other elements. These vents have been there since long before life, since then all ocean water would have passed through them more than ten thousand times, enough to seed the ocean many times over. Hydrothermal vents may well have been the laboratories that created the first metabolisms. This knowledge by itself wouldn’t specify which chemical reactions comprised the first innovation of life’s history. The best candidates are the reactions found in the oldest parts of our own metabolism, those we share not only with other animals but also with plants and microbes, including the hardy ones around the hydrothermal vents. Out of those possibilities, one candidate sticks out: a short cycle of chemical reactions called the citric acid cycle. The citric acid cycle uses ten chemical reactions to transform one molecule of citric acid, the substance that gives lemons their sour taste through several intermediates until it has completed one turn and manufactured another molecule of citric acid. This cycle does not violate any laws of physics. It cleaves the starting citrate molecule into two smaller molecules, from which its reactions build new molecules step by step, using as material the carbon from CO2 and feeding on energy-rich nutrients. Citric acid cycle can not only perform the work of building new molecules but it can also run in opposite direction and charge the chemical batteries that power life – our bodies run it in this way to create chemical energy from the food we eat.

 

Replication:

From dissipative structures and hyper cycles emerged the chain of nucleotide, ribose and phosphate that can both replicate itself and catalyze chemical reactions. This chain is ribonucleic acid, or RNA, the first sentence in the language of nature. Scientists have successfully recreated this life’s first spark in laboratory; they mixed the molecules in water, heated the solution, and then allowed it to evaporate leaving behind a residue of hybrid, half sugar, half nucleobase molecules. To this residue they again added water, heated it, allowed it to evaporate, and then irradiated it. At each stage of the cycle, the resulting molecules were more complex. At the final stage, they added phosphate. “Remarkably, it transformed into the ribonucleotide!” said Sutherland, a chemist at Medical Research Council (UK) laboratory of Molecular Biology.

There is also the famous Miller Experiment; this was a chemical experiment that simulated the conditions thought at the time to be present on the early Earth, and tested the chemical origin of life under those conditions. It was conducted in 1952[3] by Stanley Miller, under the supervision of Harold Urey, at the University of Chicago and later the University of California, San Diego and published the following year. After Miller’s death in 2007, scientists examining sealed vials preserved from the original experiments were able to show that there were actually well over 20 different amino acids produced in Miller’s original experiments. That is considerably more than what Miller originally reported, and more than the 20 that naturally occur in life. There is abundant evidence of major volcanic eruptions 4 billion years ago, which would have released carbon dioxide (CO2), nitrogen (N2), hydrogen sulfide (H2S), and sulfur dioxide (SO2) into the atmosphere. Experiments using these gases in addition to the ones in the original Miller experiment have produced more diverse molecules. More-recent evidence suggests that Earth’s original atmosphere might have had a different composition from the gas used in the Miller experiment. But prebiotic experiments continue to produce racemic mixtures of simple to complex compounds under varying conditions.

 

Membrane;

Most of the mechanism at the microscopic level is a function of positive and negative charge of the matter. The six basic elements that life is composed of are carbon, hydrogen, oxygen, nitrogen, phosphorous and sulfur, these account for 99% dry weight of every living thing. Virtually all the molecules that we are composed of are carbon based. Carbon atoms being very light and with four valence electrons (i.e. electron in outer most shell available to pair with another available electron) combine rapidly with other five elements mentioned earlier to generate a vast diversity of substances. A hydrocarbon chain linked to a group of phosphorous and oxygen atoms manifest an electrical charge on the end bearing the phosphate group and no charge on the other end. This chemical as a whole attracts water on its charged end and repels it on the non-charged end. Such chemicals, called phospholipids tend to line up side by side with each other – the non-charged ends pointing away from the water while the charged ends point down into water (this is what essentially happens when a droplet of oil enters water instantly forming a film).These and other types of lipids tend spontaneously to form into drops, secluding materials on the inside from those on the outside. They have also been shown to form double layers when waves bring two surfaces together. When this happens the charged ends of the sheet of lipid molecules point towards each other sandwiched between the non-charged ends. In this way the first membranes could have formed – the first semipermeable boundaries between “inside” and “outside”, the first distinction between self and non-self.

These fatty molecules self-organize into a tiny bubble, about the same size as a bacterial cell, a hundredth of a millimeter wide. The spontaneous self-organization is not quite that magical as it seems; if you had Cheerios as your breakfast cereal you will have seen fundamental universal forces conspiring to invoke spontaneous organization in your bowl, The oat rings want to float, because their density is lower than that of milk, gravity pushes them down, but the pressure underneath from the column of milk pushes them up. If, after first few mouthfuls, there is enough space at the surface, they will automatically jiggle themselves into a hexagonal pattern because this is the formation that allows the upward force to be distributed evenly.

It is thought that these bobble-headed phospholipid molecules would not have been difficult to find on the early earth, not because we have traces of them, but because they are easy to make with different recipes. As far as ingredients go, there is a simple sufficiency, and they make good contender for the first membrane. But as the origin of life is chemistry transitioning to biology, these prototype membranes needed to acquire complexity from their simple, self-organizing origin and are far off from a modern cell membrane. Modern cell membranes are studded with pumps and channels. Biological mailboxes, that are ion channels, lie embedded in the membrane to receive input signals from around the body and local environment and strong anchors link up neighboring cells to hold tissue together. There are five main ions (an atom or a molecule with unequal number of electrons and protons are called ions – more electrons make it negatively charged and more protons make it positively charged); sodium, potassium, calcium and hydrogen are positively charged, only chloride is negatively charged. Because they are electrically charged the movement of ions (across membrane through ion channels) creates an electric current. The difference between animal electricity and that which supplies our homes are simple – the fundamental properties of electricity were understood by the beginning of the 19^th century, it is only in the last 60 years or so that we have begun to understand the origin of bioelectricity and only in the last fifteen years that we have had a glimpse of what the molecules (the ion channels) responsible for the electrical activity of our nerve and muscle cells actually looks like.

The evolution of simple cells from membrane bound matter had taken billions of years. Most scientists think that lipids combined with proteins to make translucent packages of lifelike matter before the beginning of life itself. No life without a membrane of some kind is known.

Probably not once but several times, amino acids, nucleotides, simple sugars, phosphates and their derivatives, formed and complexified, with the energy from the sun within the protection of a lipid bubble, absorbing ATP (Adenosine triphosphate) and other carbon nitrogen compounds from the outside as “food”. Fairly complex structures have formed spontaneously from lipid mixtures in the laboratories. Bubbles of lipid split in two at first simply from the strain of surface tension, each half carrying on its internal activity. The proto-cells simply broke down and disappeared, while others formed in some other tidal pool, each with a slightly different “modus operandi”.

Many dissipative structures, long chains of different chemical reactions could have evolved, reacted and broken down for millions of years before the elegant double helix of our ultimate ancestor (Luca) formed and replicated with high fidelity. Indeed living forms based on totally different types of replicating molecules may have arisen and developed for a while before disappearing altogether. But because they are the common denominator of all life today, it is clear that at some point lipid membranes containing RNA and DNA began to flourish. The numbers of these tiny bacterial spheres increased and diminished in a process of ebb and flow. At some point before 3,500 million years ago the evolutionary tide reached the level of life as we know it – that of the membrane bounded, 5000 protein, RNA-messaged, DNA-governed cell. The Earth’s microcosm, the age of bacteria, had begun. It took one billion years for prokaryotic cell to emerge because of nature’s hit and trial (not one miraculous hit) or natural selection and then two and a half billion years for the Eukaryotic cell to evolve. How cells formed and how they work is nothing magical, if we can understand these processes which we do now to a great extent, we can understand how matter became animated – no spirits or ghosts entering or leaving bodies, it is the atomic nature of ourselves.

What makes it hard to believe that we are basically matter animated is our emotional feelings of happiness, sadness, fear, anger and our capacity to the reasoned argument. It may seem uncomfortable to consider that your thoughts and feelings are determined simply by clouds of chemicals washing through your brain and by the changing patterns of electrical activity they produce. Yet with a moment’s thought you will recognize that this is indeed the case, for drugs, hormones and diseases that alter the levels of neurotransmitters in our brain affect us deeply, transforming our emotions and our behavior. A small amount of alcohol for example may usher in a more outgoing personality, cause us to behave irrationally, or sink us into melancholy. Dopamine, one of the most crucial neurotransmitter in the brain is intimately involved in desire and addiction. Pleasurable experiences such as sex, love and food trigger the release of dopamine in the brain’s reward center which increases nerve cell electrical activity, reinforcing our sensation of pleasure and craving to have more.

Without a doubt we humans are the top product of billions of years of evolution but knowing our humble beginnings and knowing how connected all life, including us is, will keep us humble. I would like to end with a quote from Curt Stager’s book titled “Your Atomic Self”, “Every atom in your body exists only because hydrogen appeared in the universe billions of years ago, anything that has to do with water, from the green tissue of a leaf to the moist bag of cells that is your body, is here because hydrogen atoms ride oxygen atoms all over the world and tremble just so in the warmth of a hydrogen fueled sun. Hydrogen given enough time does indeed become people. How utterly amazing it is how miraculous you are, and wonderful to be able to recognize and appreciate it too.

Note: Information quoted above taken from following books;

Microcosmos by Lynn Margulis & Dorion Sagan

Creation by Adam Rutherford

Your Atomic Self by Curt Stager

Spark of Life by Francis Ashcroft

Arrival of the Fittest by Andreas Wagner