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Prologue

Every one of the myriad cells that make up our bodies contains a minute drop of seawater. Not the seawater of today but as it was at the very beginning of life, in the vicinity of the underwater thermal vents that spew minerals into the ocean from below the Earth’s crust. It was here that the first forms of life are believed to have evolved, thousands of millions years ago. The contents of this fluid, inside the cells, are the same whether it is from the cells, of the heart, the pancreas, the brain or the spleen. It contains a similar concentration of salts, such as sodium, potassium and calcium, and the same minute amount of oxygen. The nature of this salty fluid, the ‘intracellular water’, has to be maintained within strict limits. If the contents change significantly, all the various processes necessary for life will fail.

Not only is the formula the same for the fluid inside all the cells of one’s body, but it is much the same as that in the cells of every mammal, irrespective of its diet or the climatic conditions in which it lives. We have much the same intracellular water as the elephant, the rat and the hippopotamus. This is no coincidence; it is the result of a common evolutionary history. It is a story that starts at the beginning of life on Earth.

Although no one can be certain as to the exact origin of life all the evidence points to it starting in the seas that covered much of Earth about 3,500 million years ago, on the ocean floor, where it existed as an immobile slime. It has been suggested that it originated with the formation of simple chains of chemicals, including a form of a primitive nucleic acid,2 the harbinger of DNA, that crystallised out from the salts dissolved in the sea. Chemicals dissolved in water will form crystals spontaneously if the concentration and temperature is right, just as substances, such as sugar and salt, crystallise out of water at a given temperature and concentration. In order for this process to become the precursor of life it would have to have been continuous and the crystals themselves self-replicating.

What is generally accepted is that, after many millions of years, something happened that suddenly caused an evolutionary explosion about 600 million years ago. This was towards the end of the greatest ice age that the planet has ever experienced, when glaciers extended almost to the equator, the time of the so-called ‘snowball earth’. It was at this time that many forms of multicellular life appeared.

What caused this extraordinary spurt in the development of life forms? Many explanations have been offered such as a change in temperature or in the composition of the atmosphere. The high CO₂ levels that had prevailed at the time of the great freeze (some 100 times the present concentration) declined and a significant amount of oxygen appeared, for the first time, in the atmosphere. However, the most likely explanation is that it resulted from the development of the cell membrane.

By trapping a tiny drop of water within a membranous, semipermeable envelope, the cell wall, it would have been far easier for the cell to maintain a stable concentration of chemicals within its internal environment. In this way it would have been able to provide the conditions for the continuous production of the chains of chemical substances that are essential for life.

Had it not been for another remarkable event, evolution might have become stuck at this point. Single cells, or thin sheets of identical cells, could control the contents of their internal water as long as they remained immersed in the constant environment provided by the sea. Any cells that were not directly bathed by seawater would have been in danger of drying out. What made the next step in the evolution of more complex forms of life possible was the appearance of special organs to monitor changes, such as drying out, and to link these to some mechanism that would allow it to protect itself. This required a communication system to be developed.

The various steps in this evolutionary pattern are speculative, but one can make a reasonable guess as to how they came about. Some indication is afforded by studying embryonic development and the stages that animals, such as the frog, go though in their maturation process. It starts with a single fertilised cell, the ovum, and develops into an embryo containing many apparently identical cells into a stage at which cells with differing functions start to appear. This allows its maturation into a fishlike tadpole, which lives in water and eventually emerges from its watery environment as a young, air-breathing frog.

It is probable that the only form of life that was capable of leaving the primordial swamp and surviving on land was composed of one or more simple, identical cells. This form of life would have survived by absorbing water and dissolved nutriment through the thin membrane covering the cell. The main danger to its survival would have come from changes in temperature or from a drying out of the environment. This dehydrating effect would have produced changes in the local concentrations of chemicals, such as sodium, potassium, chlorine and calcium, within the cell. It is believed that it was these alterations in the local concentration of salts that initiated the process of ‘differentiation’, in which new types of cells were formed. It was this process that led to the development of more complex organisms.

With the passage of many millions of years the atmosphere became drier and temperature fluctuations more dramatic. Only those organisms that produced some means of adapting to these changes survived. Those that survived developed groups of cells that had special functions. These were the forerunners of the sensory and motor organs found in more advanced forms of life. Because of the drier environment in which they now existed, the surface of these early animals became covered with a thick skin or carapace to limit fluid loss. This impermeable covering would have prevented the organism from taking in fluid and nutriment through its surface and necessitated the development of special mouth areas through which food and water could be ingested.

As the environment dried out further and changes in the temperature become more extreme, the chances of survival depended on developing some means of locomotion to allow it to escape from a dry, hot area for a nearby site where water, nutriment and shade were available. This required some means of detecting changes in the environment, a sensory system, and a means of conveying the information from these sensory organs to the organs responsible for propulsion. For this to be possible a messenger system had to be developed.

Chemicals, acting as messengers, served this function. The first such chemical messenger must have been formed from substances that were abundant in Earth’s atmosphere at that time, such as ammonia, carbon dioxide and water. It is probable that this was either acetylcholine or a similar substance. It would have been released in response to an alarm signal from cells capable of sensing changes in the outside world.

It is quite possible that the present-day role of acetylcholine, the most ubiquitous of all the chemical transmitters in the animal kingdom, dates back to these primitive times. It would have functioned in much the same way as it does today in the clams and oysters on our seashores. In these bivalve molluscs, acetylcholine is released into the fluid bathing the tissues in response to a signal produced by touching the shell. It causes the strong muscle that closes the two halves of the shell to contract.

Even today an atavistic enzyme that destroys acetylcholine is present in the bloodstream of man. No physiological function can be ascribed to this enzyme; indeed, a number of people live perfectly normal lives without it. It is possible that its presence is a footprint of the evolutionary stage when acetylcholine was released directly into the tissue fluids.

As evolution progressed and these organisms became more complex, special structures capable of detecting changes in the outside world – such as eyes and ears – developed in parts of the body that were remote from the muscles involved in making an appropriate response. This necessitated a more sophisticated means of communicating information from one part of the body to another. This need was met by the development of cord like nerve trunks as simple extensions of nerve cells. They connect the sensory organs to the brain and carry instructions from the brain to other parts of the body.

By this means it was possible for the transmitter, acetylcholine, to be released at nerve endings some distance from the sensory organ itself but close to the sites responsible for initiating a response. Acetylcholine then became a specific transmitter, passing on the messages carried in the nerves to the muscles, heart and circulation.

The next stage in this story occurred when animal life evolved still further and started foraging for food and shelter. Newer transmitter substances appeared that helped prepare animals for this new challenge. Later still in the evolutionary development of the brain, we find more sophisticated transmitters appearing associated with the response to hunger, mood, sexual arousal and memory. However, acetylcholine continues to provide the background activity that controls the release of all of these substances.

Curare

Without chemical messengers, the evolution of complex forms of life would have been impossible. The first intimation that such a system might exist came from the French physiologist Claude Bernard in the nineteenth century. He suggested that the ultimate purpose of all the control systems of the body – which are constantly in action, although we are not aware of them – was to maintain the integrity of the bodily fluids within the narrow limits necessary for life. This he proposed was the essential condition for la vie libre – life in a constantly changing external environment.

This was the position until about sixty years ago. By 1930, evidence was emerging that the chemical acetylcholine was involved in adjusting the heart rate and that it was also released when muscles responded to nervous commands. Over the next two decades there was an acrimonious debate as to the role it played in these responses imitiating them, while others ridiculed the idea.

It was at this point in the argument that the investigation into the role of acetylcholine in muscle activity converged with studies into the way in which the South American arrow poison, curare, killed its victims. There was a continuous thread in the experiments involving curare which stretched back over four centuries. It started with the early explorers to the New World, who described the terrible manner of the death of those poisoned by darts anointed with this poison and continued intermittently until the 1930s, when its action was finally demonstrated.

This was one of those coincidences that occur from time to time in scientific investigation when a discovery in one discipline provides the means of making a quantum leap in another. In this case it was the understanding of the way curare paralysed its victims that allowed the researchers at University College in London to demonstrate, unequivocally, that the brain controlled the functions of the body by means of chemical messengers such as acetylcholine. It was a discovery that changed the face of medicine.

This story begins with the discovery of America by Christopher Columbus in 1492 and the subsequent voyages of explorers to the jungles of South America.

2 It has been suggested that primitive peptide nucleic acid reached earth on meteorites and from the large amounts of interstellar dust that rained down upon its surface after it was formed. Meteorites and interstellar dust contain a high concentration of organic chemicals, including amino acids and purines, the precursors of DNA.