Social behaviour is a complex process. Even in the world of a worm. So can one gene be responsible for a type of royalty? It seems to be the case. What scientists observed is that the Solenopsis invicta red ants have two social organisations: colonies with only one queen or colonies with many hundreds. Gp-9 protein had been widely used as a marker to determine population genetic structure in fire ant populations – hence its name: General protein-9. In 1997, a research team noticed that social organisation seemed to be governed, one way or another, by this particular protein. The question was how?

In an attempt to answer, the scientists collected a number of Solenopsis invicta red ants which belonged to mono-queen colonies, and a few from poly-queen colonies. They then had a closer look at their Gp-9 proteins. To cut a long story short, they found two Gp-9 alleles which they called B and b. To their astonishment, they then discovered that the mono-queen Solenopsis invicta red ants were all BB homozygotes, while the poly-queen ones were Bb heterozygotes. This implied that the basis of mono- or poly-queen colonies is hereditary. That is to say, the social organisation of ants – with regards to the existence of one or more queens – is orchestrated by a gene.

An ant, Nathan Walker illustrations, etc.

Courtesy of the artist

Gp-9 is in fact a pheromone-binding protein, i.e. it binds these odourless molecules which can govern the behaviour of many creatures. Humans included. Such pheromone receptors are found on the ants’ antennae and once its ligand is bound to it, it transfers it to receptors on olfactory sensory neurons, which relay the pheromone message to the brain. And what would be the message such a pheromone relays? In this case, two different messages are relayed depending on the phenotype – BB or Bb – the ant carries. A worker ant will either accept an extra queen ant in its colony or it will not. It sounds simple, yet it is not…

A BB queen has all it needs to found its own colony. It is hugely overweight and can provide for itself and its eggs. Once it has mated with a male ant – in midair if you please – it will fly off and find a nice spot to lay its eggs and look after its brethren, which will subsequently become the workers that will not only look after their queen mother but will also look after the nest and fend for her. All the possible BB queen ants the original queen mother gave birth to will be sacrificed. And if any other BB queen stumbles upon the colony, it will also be killed. This behaviour occurs by way of the ‘BB pheromones’ given off by the BB queens, which signal to the BB worker ants that any other queen must be eliminated. A sorry fate.

In colonies where many queens cohabit, the workers – like the queens – are Bb heterozygotes. How do they behave? It seems that their pheromone-detecting capacities are impaired. As a consequence, Bb red ants can ‘smell’ BB queen ants a mile off and they’ll kill them. However, these same heterozygous ants miss the Bb queens because they can’t detect them. So poly-queen colonies seem to exist simply because Bb ants don’t have the means to smell them. And the bb homozygotes? These ants are not viable – they are also very skinny – and die before they are sexually mature. What is more, Bb queens are far leaner than their BB counterparts and would not be able to form their own colony without the help of workers. So royal chubbiness also seems to be related to Gp-9!

On the molecular level, not much is known about Gp-9. It probably acts as a homodimer. However, its 3D structure is still misunderstood and besides imagining that the two alleles – B and b – probably engender two different binding structures, their architectural difference is still a blur. A number of the mutations which create the two distinct Gp-9 alleles most probably affect the ligand pocket region. The B allele would be intact, while the b allele would be faulty. This could explain why the BB homozygotes are very good at smelling out the BB and the Bb queens, whereas the Bb heterozygotes can only cope with the BB queens but are not fine-tuned enough to spot the Bb queen pheromones.

Much has yet to be understood but the discovery is paramount and perhaps even a little disturbing. Here is a gene – Gp-9 – that orchestrates social behaviour. Not only does it define whether a red ant will be part of a mono-queen or a poly-queen colony – with all the interactions this implies – but it also plays some part in the chubbiness of the queen. The obvious question is: Is there any form of human social behaviour which is driven by genes solely? Or do we have our say in matters? Does free-will really exist? The usual answer is: Human social interaction is so complex that there is no way that any one form of behaviour could be pinned down to one gene. And the environment also has its say. But before the role of Gp-9 was uncovered, the same was said about ants. The wonderful thing about humans though is that we all own that beautiful talent called imagination which we can use to ensure us of our freedom. Gp-9 or not.

It all started in May 2007 when we thought that it might be amusing to imagine an outdoor exhibition where visitors could stroll – one way or another – along the human genome and, in so doing, discover the world of DNA, proteins and bioinformatics. Our fist idea was to make the exhibition 3 kilometres long thus representing the 3 billion base-pairs which make up the human genome. The best distance available in Geneva for such an endeavour was the edge of the lake – a walk which would take the visitor from the Museum of the History of Science to the botanical gardens a little way down the road.

We presented our project to the botanical gardens who were very enthusiastic but rapidly demonstrated that an exhibition which spread over such a distance presented a number of drawbacks. Not everyone is keen to walk so far for the sake of culture, and after a panel or two, they would probably lose interest and peel off the track to enjoy the lawn. What is more, how do you make people start at the beginning of the exhibition? Anyone out for a Sunday afternoon walk saunters down from any part of the park. What if they bump into panel no.11? Are they going to walk back to panel no.1? Probably not. The major drawback though was the World Trade Organisation. This majestic building poised on the lake’s edge was built between the two museums. And when it organises conferences, the part of the lake it faces is shut down and no one is allowed through. This would have cut our exhibition into three, the middle bit of which would have been out of bounds.

So we opted for an exhibition that would be mounted on the grounds of the botanical gardens only, where – in a classical fashion – the point of departure is also the point of arrival. Like old ways though, obsessions die hard. The exhibition could not cover the distance of an unravelled genome but surely there were other ways of expressing DNA quantity and length? We agreed upon creating 23 different panels to illustrate the 23 pairs of chromosomes found in the nucleus of most of our cells. Each panel could have a different size reflecting the size of the chromosome… Or panels could be placed in such a way that the distance between them is proportional to the amount of DNA in a chromosome… And if helium-filled balloons were fixed onto each panel, the length of the string holding them could be proportional too. And the balloons themselves could echo the size of a chromosome… There was no end to our imagination. However, our imagination turned out to be costly in many ways and it took the patience and subtle persuasion of a graphic designer and some understanding on behalf of eager scientists, to realise that the quantity of DNA in chromosomes was of sweet indifference to the layman. And in time, the idea was abandoned altogether.

Once the basics of the exhibition had been agreed upon – i.e. 23 panels for the 23 pairs of chromosomes plus an introductory panel – all that was needed was to find what we were going to put on them. It seemed pretty straightforward in the beginning but things are rarely so simple. The following months witnessed a fierce battle in the name of Science and how to express it. Eager to see the positive side of things, it was a unique opportunity to fine-tune the concept of ‘popular science’. It started out as an interesting experience, where it was discussed how to say things best by tossing concepts, adjectives and commas into the air. However, the discussing soon became a form of polite controversy and more often than not the end result lay in a no-man’s land of vocabulary, syntax and grammar where both the scientists and the writers felt fairly satisfied though neither were really convinced.

More often than not, scientists would introduce an obscure concept using words only known to themselves to which they would add nuances and exceptions which harvested confusion. The next step was to shed light onto the darkness. It was fun and creative to begin with but, in the long run, the process became tedious, infuriating and nerve-racking, though also comical. In an attempt to see the bright side of things, every one was making an effort to understand the other. However, good nature has its limits. And dark clouds accompanied by claps of thunder and flashes of lightening occurred regularly.

In spite of this, or indeed thanks to this, our exhibition has turned out to be an elegant succession of colourful and informative panels from which float graceful helium-filled balloons in the shape of chromosomes. Each panel presents one human chromosome and a number of genes found on it. It then goes on to illustrate an aspect of the world of DNA, proteins and bioinformatics, and there is even a special space reserved for children. So, by the end of the exhibition, visitors should have a fair idea of what genes and proteins are, and how bioinformatics has helped in their understanding.

The exhibition turned out to be a huge project and it has been worth it. This said, we are still seeking for sponsors. Indeed, some have been very generous but we haven’t managed to cover the costs yet. After Geneva, the exhibition will be going to Lausanne, and a number of institutions in England and the United States of America have already expressed an interest. Besides the layman, the exhibition is also a great way of introducing the world of biology and computer science to adolescents seeking future careers. And it is our sincere hope that our Chromosome Walk will not only help many understand the minute world that is the basis of Life but that it will also trigger off a few callings.

Everyone has heard of stomach ulcers. Many have also heard that stomach ulcers are caused by stress. Not everyone knows, though, that many stomach ulcers are the result of H. pylori infection. It took a long time for the scientific community to believe that any living organism could survive within the depths of our digestive system. The environment is far too acidic. It required that a scientist drink a potion of H.pylori and develop gastritis which was successfully treated with antibiotics. Once it had been demonstrated that bacteria could indeed survive in our guts, the question was how?

H. pylori likes to live in the mucus gel layer which lines the stomach. It gets there by using its flagellum and is able to remain and survive there by reducing the surrounding acidity thanks to the enzyme urease. Urease achieves this by breaking down urea into carbon dioxide and ammonia. In doing so, the enzyme not only reduces the local gastric acid but also produces a source of nitrogen for itself. Concomitantly, it weakens the mucus coating. Acid is then able to reach the sensitive lining underneath and corrodes it, causing discomforts such as an ulcer.

Helicobacter pylori

H.pylori Research Laboratory
Nedlands, Australia

H. pylori was first observed in humans in 1875 by German scientists. They didn’t manage to cultivate them however and no one took any further notice of it. In 1899, Polish researchers mentioned in an article that a number of gastric diseases could well be due to the bacterium – but Polish, like today, was read by very few. Fortunately, in 1981, two Australian scientists – fluent in English – managed to both cultivate H. pylori and demonstrate that the bacterium could indeed be the cause of stomach ulcers and gastritis as opposed to stress or spicy food. However, it took a further decade before the medical community actually recognised the fact and added antibiotics to the treatment of ulcers and gastritis.

Like H. pylori, it took years before urease was taken seriously. In the early 1900s, it was common belief that enzymes were not proteins and constituted a very minor part of any organism, so there was no point in trying to isolate them. Despite this, an American chemist, James Sumner, decided to ignore reasoning that only hindered the advancement of knowledge and, with the help of a coffee mill and a mortar and pestle, he took to grinding jack beans. His success was far from immediate but by 1927 he had not only demonstrated that an enzyme was a protein but he had also managed to crystallise the first enzyme ever: urease. And since we are on the subject of exploits, not only was urease the first enzyme to be crystallised but it was also the first nickel-containing enzyme to have been discovered.

In short, ureases are found in bacteria, yeast and a number of plants. This enzyme helps H. pylori – as well as some other bacteria – survive in our stomachs and is an assembly of heterohexamers. Most ureases are an assembly of three hexamers composed of 3 heterotrimers of alpha, beta or gamma subunits (αβγ)3. The H.pylori urease, however, is a super assembly of four hexamers of alpha and beta units (αβ)3 – where the beta subunits are in fact a fusion of the alpha and the gamma subunits found in other species. The resulting complex is huge! The bigger the better it seems since it is believed that the huge size of the H. pylori urease may make it more stable.

This molecular stability is not good news for humans on two fronts. First, the more stable the urease is, the better H. pylori will be able to infect us. Second, it is always a more difficult task to design drugs to counter molecules that are sturdy. However, as always, the more we know about the structure and function of urease, the greater the chance will be of finding an adequate treatment against common ailments such as stomach ulcers, gastritis and certain forms of cancer.H. pylori and urease are beautiful examples of research which were confronted with scientific scepticism and narrow-mindedness, and demonstrate that what was thought to be of little interest turned out to be at the heart of groundbreaking events.

Discovering an odorant receptor is nothing new. Major discoveries of the like were made almost twenty years ago. What is singular, though, is that for the first time scientists are able to link an odorant receptor to a specific ligand. This is a breakthrough because, unlike our visual and hearing senses which are relatively straightforward, our olfactory senses are part of a highly complex system. We know what light frequency will give which colour. And what sound pitch will give which sound. But no one can say ‘this molecular structure will give that smell’ – which would be the perfume maker’s Holy Grail. What is more, knowing a molecule’s structure is not sufficient. Any smell is the combination of more than one odorant molecule.

There are thousands of different smells and we are capable of discerning each one of them. Yet the human capacity to sniff out stuff has slackened over the millennia because we have put both our hearing facilities and our visual capacities to a greater use. As a result, our olfactory system is now one third of what it probably was in our ancestors. A rat, for instance, expresses about one thousand olfactory receptor genes, while we only express about three hundred. These olfactory receptors are found in ciliary membranes immersed in a film of mucus which lines the inner side of our nose. The cilia are the tips of sensory neurons which relay a smell along their axons to the brain. The brain will either recognise the smell it has just received – and consequently so will we – or it will discover a new smell and memorise it for the next time.

‘Woman smelling coffee’ by Gizem Sake

Courtesy of the artist

To cut a long story short, a specific scent is made up of a certain number of odorant molecules. Each molecule will bind to a specific receptor found on the surface of a sensory neuron. One molecule can bind to more than one species of receptor. Likewise, one receptor is able to bind more than one molecule. Consequently, one smell can set a whole network of neurones shivering and relaying messages to the brain. The brain sums them all up and can either come up with an immediate answer such as ‘coffee’ or, if the smell is unknown, whatever it is we have just smelled will be remembered and a direct link will be made to it the next time we get a whiff of it.

OR7D4 is an olfactory G-coupled receptor similar to all those known to date. It is a transmembrane protein, with an extracellular loop, which acts as the binding pocket for its ligand, and a cytoplasmic domain which reacts with the G-protein. Androstenone, which is an odorous steroid derived from testosterone, lodges in the OR7D4 binding pocket thereby changing the receptor’s conformation. This triggers off the formation of cAMP thanks to the G-protein, which in turn opens a channel protein. The opening of the channel lets in cations which change the neurone’s membrane potential, and this is the very beginning of an electric signal which is relayed, along the sensory neurons’ axons, all the way to the brain that will read the message as being part of a smell.

Discovering a ligand’s receptor is one thing. Attributing an actual smell to a specific ligand is another. It seems to be the case with androstenone though. This is a smell which is usually perceived as unpleasant (urine- or sweat-smelling), pleasant (sweet- or floral-smelling) or without a smell. That would make three smells, you’re thinking. Not really. It is one smell perceived differently. What is it that makes people smell a smell differently? Is it innate? Or does it have something to do with something far less tangible, such as personality, past experience, or even the subconscious? Many will answer that, though there is no doubt a genetic basis, much must be due to something which is not inherited. In the case of androstenone, however, there may be a case of an inherited difference in perception. Indeed, there is a common variant of the OR7D4 receptor and it seems that individuals that carry the same variant tend to smell androstenone in the same way…which would point to the genetic inheritance of a smell…

A lot of time and money is spent cracking the scent code. Besides the perfume industry, there are plenty of other industries that need smells to sell. Food, cosmetics, washing-up powders and beverages – to name a few – all make use of the power of fragrance. The industry has even learned how to trick our smelling senses. Take synthetic lemon juice, for instance, which only uses a few of the chemicals found in natural lemon scent and yet we can identify it as lemon. A handful of scientists have suggested that a crude quality of a smell, such as its pleasantness or unpleasantness, is simply a case of molecule compactness. So the more compact an odorant molecule is, the nicer it might smell. However, it is also known that one same odorant molecule can smell nice when there isn’t too much of it, and awful when there is a lot. Take indole for example which is an odour molecule found abundantly in faeces and yet it is used in very small amounts in perfumes… Inherited or not, purely for our survival or not, what a smell will never be able to take away from us are the beautiful memories – and no doubt the bad – they are able to stir in us.

Sperm have been fertilizing ovules for millions of years and yet we are only just beginning to understand the rudimentary fundaments involved. Over the millennia, the miracle of conception has occupied some of the most learned minds and, before the existence of the microscope, a vivid imagination was required to make sense out of the liquid men injected into women, which ultimately produced a new version of one of them. A baby boy or a baby girl. Hence the existence of what may seem preposterous theories to us now but which were perfectly sensible in the light of what was then known. For instance, two opposing schools of thought lasted for a very long time. There were those who believed that a complete – but very small version of a human – was contained within one sperm and, once in the woman’s womb, it grew to the size of a newborn. And then there were those who believed that a perfectly-shaped baby human was already floating in the ovule and that all it needed was the sperm to trigger off its growth.

Despite an apparent simplistic view of how Nature dealt with things, what had been understood is that both a sperm and an ovule are necessary for conception. Nothing happens in the absence of the other. And that remains a fact. What we know today is that both gametes can be present and, what is more very close to one another, but if there is something faulty on either one’s surface, nothing will happen. And this is frequently the cause of infertility – male or female. Gametes have a very specific and intricate makeup. There are molecules on their surface which have a protective role, molecules which recognise the other and molecules which allow them to adhere to one another. Zp3 – for zona pellucida 3 – is a protein receptor which is buried in the matrix which surrounds an ovule, known as the zona pellucida. This is the cushiony part of the cell, full of carbohydrate and protein in almost equal amounts, through which one sperm must find its way to initiate fertilization.

‘Tenderness’ by Vladas Velyvis

Zp3 is a cell surface receptor which is bound to the ovule’s membrane. Typically, the protein backbone of zp3 is covered in O-linked oligosaccharides which make up part of the zona pellucida cushion. These particular carbohydrates are recognised by a receptor found on the sperm’s surface. Despite this recognition, scientists believe that the binding of a sperm to an ovule also involves a host of other molecules. What is clear though is that zp3 and its oligosaccharides are needed to initiate the acrosome reaction – the reaction in which the sperm binds irreversibly to the ovule’s membrane and, in so doing, triggers off the chemical process which modifies the supra-molecular structure of the zona pellucida thus forming a barrier to the entry of a second sperm.

Besides discovering the beauty of how life starts on a very small scale, the finer our knowledge is on the molecular processes involved in the moments before and during fertilization, the better we can help men and women faced with infertility problems. Similarly, targeting essential molecules on the surface of sperm or ovules could lead to alternative methods of contraception. Research of the kind has been carried out in the hope of checking the exponential growth of animal populations. Protected from ivory poachers and squeezed into geographical spaces that are getting smaller all the time, elephants are overpopulating game reserves in Africa. Instead of shooting them, a means of birth control would be a more humane solution. Since the 1990s, scientists have been seeking ways of producing antibodies to zp3 for instance, which would create temporary infertility. Some have suggested engineering a virus with a copy of human zp3 and intentionally infecting an animal species whose growth has gone out of control. For instance, mice infected with the virus would produce zp3 antibodies, thereby causing infertility of their host because mouse zp3 is very similar to human zp3. Furthermore, one mouse would infect another mouse, and each infected mouse would in turn become infertile. The problem is: who says the virus won’t infect another animal population which is essential to the fauna’s equilibrium… It is a risk which cannot be taken.

Likewise, immunity of some kind against zp3 could be an elegant form of contraception for humans. It is common knowledge that, though very useful in many ways, the pill or intrauterine devices can be damaging to women – so any method which could prove to be absolutely harmless is welcome. Recently, some scientists suggested a gene-silencing technique whereby the zp3 gene is not translated. This is done by using a method known as RNA interference. In this case, short RNAi fragments bind to zp3 mRNA thus checking zp3 translation. Consequently, the zp3 receptor does not appear on the ovule’s surface and sperm are then unable to bind to an ovule – which is a sure means of avoiding conception. This kind of contraceptive could be administered through a skin patch or by means of a vaginal suppository. And scientists are confident that such treatment will only affect the zp3 receptors of maturing ovules – i.e. the ones that make an appearance once a month – and not the whole reserve in the ovary. It sounds promising and attractive. And far more appealing than a chastity belt.

Every single dog the human race has ever known not only belongs to the same species, Canis familiaris but is also descended from only one other species: the grey wolf, Canis lupus. The variation in size – which no other mammalian species has experienced – results from the selective breeding of dogs over the years and can be tracked all the way back to the beginnings of animal domestication. Medium-size dogs are probably more popular because they are easier to look after. Likewise, if a dog wants to be part of a household, it is better off medium-sized. Fossils, the size of Great Danes or of terriers, date back thousands of years. However, the huge variation we can testify to on a daily basis – from pocket dogs that hardly weigh a kilo to a hundred kilo Saint Bernard – is the result of strong selective breeding which has taken place within the past few hundred years only and has produced an array of 350 declared breeds.

Whatever it is that has made dogs small has been present for a long time. Scientists discovered an insulin-like growth factor 1 (IGF1) variant that is widespread in small dogs meaning – on evolutionary terms – that it was fixed in Canis familiaris many years ago. It is not present in the grey wolf’s genome and the early appearance of the IGF1 variant will have driven the rapid genesis of size diversity in the domestic dog. What is more, this particular variant is geographically widespread – most probably as a result of trading and human migration – thus supporting the fact that it appeared early on in time.

‘Skinny Vinny’ by Lisa Ballard

Dream Dog Paintings

Courtesy of the artist

A study was carried out on one particular breed of dog – the Portuguese water dog. The samples varied substantially in size due strong selective breeding. What the scientists discovered was that every single small-sized dog carried the IGF1 variant while the larger dogs did not. They then turned to other dog breeds to discover the same thing: all the small dogs carried the variant. Although most of the bigger dogs did not, a few did. This means that there is a ‘stronger’ mechanism which exists to dictate the size of larger dogs. It also means that size – like all other phenotypes – is defined by something far more complex than the mere action of just one protein.

insulin-like growth factor I promotes the growth of an organism by firing off a network of reactions – loosely known as the IGF pathway – which ultimately promote protein turnover, cell proliferation, tissue differentiation and even protection against cell apoptosis. Upstream, IGF1 action is triggered off by the pituitary growth hormone, or GH. IGF1 is at the heart of an organism’s maturity. It is synthesized in the liver from where it acts on a wide variety of tissues and mediates its action by binding to its receptor. This launches multiple IGF1 signals transduced by way of phosphorylation reactions to hosts of kinases downstream. IGF1 exists in two forms. It can either bind directly to its receptor or bind to IGF-binding proteins where it is buried in a protective envelope, thus delaying and modulating IGF1’s interaction with its receptor.

Besides finding a way to fit a dog into a matchbox, what is the point of such studies? Such a huge variation in a phenotype within one same species provides valuable information on two fronts. On the one hand, it can reveal how key elements are involved in intricate pathways and, on the other, it can give an idea as to how sets of genes interact to come up with a specific phenotype such as size, or even behaviour. The Canis familiaris model is also precious for the analysis of genetic polymorphism and the understanding of the differences between a healthy genome and a pathological one.

The IGF pathway has been under close scrutiny for some time. Not only is it involved in an organism’s maturity but, unsurprisingly perhaps, it also seems to play a part in an organism’s longevity. A faulty IGF, or indeed, a faulty receptor is likely to create some kind of havoc. One interesting study was carried out on a number of women with a faulty IGF pathway, who had not only lived to be a hundred years old but whose stature was slightly under the average, echoing the effect the IGF1 variant has on dog breeds… Do small dogs live longer than big dogs? The issue was not raised. Though there are no doubt many handbags out there that would enjoy the knowledge that they will get old with their closest companion.

Humans are particularly clever with their hands. One of the very first special events in our evolution was to get onto our hind limbs and free our hands for collecting food and making tools. A subsequent good move was to take away the burden of communication on our hands by developing our vocal instruments. Indeed speech, and its fine-tuned elaboration that only humans have managed to master so far, has given our hands great freedom which we have put to use in a multitude of ways. But none of this can explain why we are – for the great majority (90%) – right-handed. Hosts of other species also use their appendages for collecting food, eating or grooming but they don’t have a distinct preference for one hand over the other.

The passing of roles from hand to mind expresses a particular brain structure. In turn, the progressive use of speech has continued to mould our brain into a shape peculiar to the human species. But why would that make us right-handed? For speech to evolve, one part of our brain had to evolve differently too, and in so doing it made most humans right-handers. This is what is known as the ‘right-shift factor’. Consequently, our right-handedness is not the result of nature selecting right-handers over left-handers but rather of nature nudging our brain into a shape which encourages the act of speaking. As a result, over the millions of years, the human brain has been divided into two hemispheres. The right hemisphere is dedicated to the world of emotions and imagination, whilst the left hemisphere deals with talking and logical processes.

Two men engaged in conversation

Source unknown

LRRTM1, or leucine-rich repeat transmembrane neuronal protein 1, is a protein involved in brain development. It has a set of repetitive domains in its sequence which are known to be involved in protein-protein interactions, a vital activity in the light of brain structure and development. LRRTM1 may be one of the factors which bestows upon the brain its asymmetry. It is expressed very early in the development of forebrain structures and may function in neuronal differentiation and connectivity. It is also thought that it could have a role in intracellular trafficking in axons. Left-handedness, which is handed down by the father, may well be due to LRRTM1 dysfunction causing the original asymmetry to be flipped around, or reduced. However, it has been pointed out that chimpanzee LRRTM1 is 100% identical to human LRRTM1, yet no one has found a left-handed chimp, or an articulate one for that matter. Handedness and subtle brain asymmetry, as found in humans, are the result of much more than just one protein – and environmental factors are undoubtedly of great influence too.

With a role in brain development and possible neuronal connectivity, it is hardly surprising that LRRTM1 has been linked to neuronal diseases such as schizophrenia, autism and language impairment. Likewise, a logical step was to wonder whether left-handedness could not be taken as an indication to a predisposition for neuropsychiatric disorders. It so happens that in one study carried out on schizophrenic individuals many were left-handed. This kind of result has to be taken with caution though. It does not mean that every left-handed individual is prone to some form of psychosis. Many right-handers suffer from psychiatric impairment too. However, it does suggest that genetic components involved in the structure of our brain may be indicative of a predisposition to a neuronal illness, given the environment. Surprisingly, other studies have shown that left-handers are more prone to accidents than right-handers. No clear explanation has yet been given but it may just be because our society is really built for right-handers.

LRRTM1 is predicted to link to another protein – or proteins – where the bond would supposedly trigger off a reaction. With this in mind, if it can be shown that LRRTM1 does have a role in the development of neuropsychiatric diseases, it may well prove to be precious in the design of novel therapies to lessen such disorders. Once again though, no protein acts on its own. There are genes upstream and downstream of LRRTM1 involved in its expression. Furthermore, an individual’s environment is hugely important in triggering off a psychiatric disorder: drugs, alcohol, abuse, violence, stress etc. And, besides psychiatric disorders, what to think of someone who writes with their left hand and throws with their right? What is their brain structure? Is LRRTM1 also part of semi left-handedness? It is all very mysterious. But the fascinating part of the story is to realise that were it not for our words, we would not be able to carry out nearly as much as we do with our hands.

Why make a meal out of your kin when you have the option of surviving – albeit in a slow-motion form – as a spore? Sporulation occurs when the environment does not provide sufficient nutrients for micro-organisms such as Bacillus subtilis, for example, to survive. Though the aim of sporulation is to prevent cell death by enclosing it in a micro-environment in which the minimum is provided for a creature living at a minimum pace, the process is extremely energy-consuming. Sporulation calls on the activity of over five hundred genes, involved in complex molecular pathways. Once the first steps have been completed, the morphogenesis of sporulation is irreversible. When the environment becomes plentiful again, unraveling the doings of sporulation is just as energy-consuming before B.subtilis can settle down and feed. So if sporulation can be sidestepped, it is.

One way of doing it is to make sure B.subtilis has enough to live on. If it doesn’t, the next step is to delay sporulation as long as possible, just in case the conditions get better. Indeed, a non-sporulated bacterium will profit from bountiful surroundings much faster than a sporulated one. As a consequence, non-sporulated B.subtilis are far more favoured. In stark conditions, one gruesome way of putting off sporulation is by eating those closest to you. Though unicellular, B.subtilis is relatively sociable and frequently evolves in small colonies. When conditions become life-threatening, a number of the cells in the colony are thrust into the process of sporulation while the fate of the others – over two thirds of the whole colony! – is to be lysed and digested.

© Michael Leunig

Used with permission

Two proteins directly involved in this peculiar homicide are the sporulation killing factor, SkfA, and the sporulation delaying protein, SpdC. Cells which are not directed towards sporulation and whose fate is to become bait, produce neither SkfA nor SpdC. Both toxins are produced when B.subtilis enters the first steps of sporulation – steps which are not yet irreversible. Very little is known about the two proteins and their mode of action, besides the fact that without them, there would be no cell lysis, and hence no food supply.

Both proteins are toxic and secreted into the environment. SkfA is secreted by way of a pump which also only appears in sporulating cells. Being specifically pumped out of a cell may be one way of shunning suicide. Indeed, if SkfA can kill off identical cells, it can also kill the one which made it. It’s like turning your own weapon onto yourself. SpdC is also secreted. It is still unknown how but more importantly its existence seems to stimulate the production of an immunity protein known as SpdI which protects the sporulating cell from doing itself any damage.

How SkfA and SpdC lyse the sister cells remains a mystery. It may be that they are merely intermediate and that it is another molecule that is actually responsible for lysis. Perhaps they disrupt the cell membrane some way or another, either by lodging themselves inside it and causing molecular chaos. SpdC acts as a ligand and the attacked cell may have an SpdC receptor on its membrane. SpdI – which is only stimulated in sporulating cells – may act as an immunity molecule, either by binding directly to SpdC in the sporulating cell so that it doesn’t get the chance to bind to its receptor, or by binding to the SpdC receptor so that there’s no room for SpdC. Either way, the sporulating cell is saved from self-attack.

There are many unknowns in this peculiar bacterial cannibalism. Since B.subtilis assembles in colonies, the process can be seen as a form of programmed cell death where – in close proximity – a number of cells are sentenced to death in order to save others. It is also a singular case of chemical warfare – a very well documented event amongst distinct bacterial populations. In fact, SpdC and SkfA may enjoy a far broader toxicity than their own species. Especially if they can disrupt a cell just by squeezing into its membrane. Evidently, more time is needed to unravel the mystery of B.subtilis vs B.subtilis. And why see it as a way of avoiding sporulation? Perhaps feeding on sister cells is less to delay the process than simply to make sure that sporulation is completed – since it takes up so much energy. You wouldn’t want to find yourself half-sporulated with no nourishment to finish off the job… In which case, is it not more a case of altruistic martyrdom than cannibalism?

Keeping our balance is not such a simple task. You may think that it’s all a question of a little concentration and crafty positioning of the body. But it’s not. There is more to it than that. We have built-in devices which we need not only to keep an upright posture but also to sense movement. These devices are known as otoconia and are located in the darkest recesses of our inner ear. Otoconia are a mixture of organic and inorganic material. In humans, their size ranges from 3 to 30μm and they are bathed in an extracellular gelatinous matrix. The otoconia themselves have an organic protein core cloaked with calcium carbonate (CaCO3) crystals – a bit like the sweets our grandmothers gave us, which were hard on the outside and filled with a soft centre.

Otoconia synthesis is completed shortly after birth. Caught in an extracellular gelatinous matrix, itself packed full of protein, this peculiar biomineral cum protein mass forms a jelly-like membrane which rests on tiny hairs. These hairs are embedded in two small organs of the inner ear, known as the utricle and the saccule. Any movement of our head – with respect to acceleration or gravity – makes the otoconia move. And since they are resting on the hairs, their movement will, in turn, cause the hairs to move. The perception is then relayed to nerves which will make a point of telling the brain. The utricle is largely horizontal and will register any movement in the horizontal plane, such as acceleration. The saccule, on the other hand, lies in a vertical plane and registers movement due to the pull of gravity.

Ocean perch (Sebastes mentella) otoliths

Source: Wikipedia

Otoconia are formed during embryogenesis and their final design is completed shortly after birth. Otoconia seedlings are probably secreted into the extracellular matrix, and are most likely to involve a core protein matrix which is calcium-friendly. Calcium and carbonate concentration must also be heightened in the seedlings’ vicinity, so that the calcium carbonate crystal envelope can be shaped. Otopetrin 1 is part of the gelatinous extracellular matrix in which the otoconia float. When otopetrin 1 is deficient, the formation of otoconia is impaired. As a result, the perception of acceleration and gravity is confused, and mice carry tilted heads or zebrafish swim upside down.

Otopetrin 1 has all the characteristics of an integral membrane protein, yet it is found in the extracellular gelatinous matrix. This has led scientists to believe that the protein is most probably imbedded in the membranes of vesicles which bud off epithelium cells. In zebrafish, otopetrin 1 seems to be involved in protein transport, and in particular the trafficking and localization of a protein known as Starmaker. Starmaker is proving to be essential both for the fashioning of the fish biominerals – known as otoliths – and the crystal lattice on which they grow. Otoliths are of the same nature as otoconia, only far bigger. While we own many otoconia, fish only have three. But they are large, mainly because the deposit of calcium carbonate only stops when a fish doesn’t need a sense of balance anymore. Though a role in protein trafficking has not yet been witnessed in humans, otopetrin 1 does seem to be involved in calcium regulation in response to ATP. However, otopetrin 1 itself doesn’t sport domains that, until now, have been known to interact with ATP or calcium. Consequently, either otopetrin 1 activates proteins that do, or its sequence contains atypical domains that can! Whatever the outcome, otopetrin 1 is certainly essential for the formation of calcium carbonate crystals, and hence otoconia.

Otoconia – or the lack of them - can be the source of trouble. The passing of time can cause the structures to degenerate or change position. The sensation perceived is known as benign paroxysmal positional vertigo (BPPV) and, though harmless, those concerned suffer from dizziness or loss of balance. The elderly are prone to falling which frequently results in broken bones or even, sometimes, accidental death. Certain drugs can also be the cause of otoconia degeneration and patients suffer from the same disorders. Research on otoconia and otholiths is now focused on finding therapies which could improve their stability over time as well as enhance the biomineralization of remaining otoconia. Otoconia regeneration is also being considered. Furthermore, getting to know the mechanisms involved in otoconia synthesis could lead to a better understanding of how bone (CaCO4) is made – and without bone or otoconia, how could we fully enjoy a balanced life?

On the occasion of Amos Bairoch’s 50th Birthday

Life has its ways. We are given opportunities to make choices. We are even given opportunities to nudge life onto a path we wish. And yet, there seems to be an invisible force lurking beneath which leads you to the most unexpected places…an unexpected place which, in time, turns out to be the place where you should be. Call it destiny, perhaps. Today, fifty years after the day he was born, Amos is sitting in an office in Geneva at the head of a project which has travelled around the world and for which many people work. From a cramped attic to a large open space office, Swiss-Prot continues to grow both in work force and in use. Amos has won prizes for it. He has been praised for it. He has put much of his soul and his heart into it. And despite this, far from him was the desire of ever having really wanted it.

New path, Meg Harper

Courtesy of the artist

The story has been told many a time. Over twenty years ago, while working on his thesis, Amos felt the need to sort and perfect a protein sequence databank which already existed. And he did. Instead of listing the sequences of proteins, he felt it was of greater benefit to the scientific community to offer some information on the protein as well – such as its structure, its function and its possible involvement in illnesses. Having done so, he offered to those concerned what he saw as improvements made to the existing databank. No particular enthusiasm was shown for his effort, so Amos undertook to develop his concept, fully expecting to hand it over to someone else so he could get on with things he was more interested in, such as exobiology.

But that is not the way the wheel turned. Protein sequences kept on pouring in and, though the rate of submission was far slower than it is today, Amos took it on himself to maintain the rhythm. As a result, he continued not only to enter them manually into his embryo-databank but also to annotate them. There was little point in dropping something that was proving to be useful. That was the beginning of the…beginning. It was not long before he needed help to cope with the profusion of incoming data. And ever since, the number of scientists who strive to keep pace with automated sequencing and a competitive knowledgebase, has never ceased to increase. Today, Amos is surrounded by computer scientists, biologists of all walks of life, secretaries, receptionists, science writers and science communicators. And a lot of us are sitting in a big modern office in the basement of Geneva’s academic medical centre where it all started, whilst others are scattered in other parts of the world.

Hundreds of fingers boogie – or mooch – across keyboards every day, for the sake of proteins. Dozens of pairs of eyes scan computer screens every day, for the sake of proteins. Millions of neurons spark – or indeed fail – every day, for the sake of proteins. Numerous cups of coffee are absorbed, thousands of words are exchanged, hordes of paper are printed, hundreds of footsteps are made, hearts beat, lungs breath, sighs are lost and a few aspirin are swallowed – every day, and all for the sake of proteins.

And, in the hands of experts, these singular molecules of life are given a name, brought down to a sequence of letters, sorted into families, sculpted into space and predicted a role. They are fashioned into ribbons, moulded into globes and painted in the colours of a rainbow. They are explained by professors, sought after by researchers and discovered by students. Pharmaceutical companies commercialise them. Journalists write about them. Artists weave them, sculpt them and paint them. All of us, without exception, eat them. And, what is more, we make them.

Without proteins, life would not exist. And neither would any of us. Without proteins, Swiss-Prot would never have seen the light of day. Neither would Amos for that matter. 50 years ago and a little more, proteins were hard at work in that little spermatozoon which wriggled towards its mate. When it reached its other half, dozens of proteins made quite sure that no other would get a chance. A cell was born. The first. The very beginning of a human being. And from there, with the help of billions of proteins, millions and millions of divisions occurred. Proteins supplied energy and ferried chemicals, they triggered off pathways and monitored rates, transcribed DNA and translated RNA, built networks and provided heat. They let a heart beat, ears hear, eyes see, legs walk and they designed the mould from which a mind could grow. Undoubtedly, there is not much we would be without these remarkable molecules. And destiny? Could destiny also be in the hands of proteins? Hardly. But they certainly do have their say. ]]> Swiss-Prot cross references

The expression of a gene is dependent on so many different instances, from the presence of a certain ion to a specific moment in development. However, until recently, it had always been thought that transcription factors had the last word. They were the ones who decided whether a gene would be transcribed and ultimately translated. But it is not so. Tiny strands of RNA – known as microRNAs or miRNA – are beginning to raise their voices and show that they are just as good as any transcription factor. The concept is mind-blowingly simple: miRNAs recognise their complementary sequence encoded in a specific mRNA and bind to it. In so doing, they interfere with the proper translation of the mRNA sequence and no protein product is synthesized. It’s a bit like immobilising a locomotive on a railway, thereby hindering the passage of a train.

The knowledge that certain non-coding RNA molecules – the miRNAs – were actually part of protein expression regulation arose in the early 1990s whilst working on Caenorhabditis elegans. Since then, many different miRNAs have been discovered in animals and plants – and the viruses that infect them – and it is becoming obvious that their role in protein expression regulation is important. It is thought that the human genome may well house up to 1000 miRNA genes, which could regulate as many as one third of our protein-coding genes…which is not trivial.

3D structure of Dicer

Source: Wikipedia

Lending the silencing of genes to the sole existence of miRNA is, however, a little short-sighted. In truth, they need a battery of enzymes to meet their ends. Drosha and Dicer are two such enzymes, whose major role is to cleave RNA. The making of mature miRNA – which is the RNA strand that actually recognises its target – is part of a fascinating process. Drosha, like Dicer, carry two domains in their sequence known as ribonuclease III (or RIII) domains. Thanks to protein sequence folding, these two domains meet to form an intramolecular dimer which – in both cases – is the catalytic site for RNA processing.

Drosha is found in the cell’s nucleus and specifically recognises primary miRNA (pri-miRNA). Drosha – like Dicer – can only recognise double-stranded RNA so, conveniently, pri-miRNA folds into a hairpin conformation thus producing one double-stranded end. The two RIII domains form a cleft into which the RNA hairpin can lodge. Drosha then cleaves one end to produce what is known as pre-miRNA. Pre-miRNA is then shuttled out of the nucleus where it encounters Dicer. Dicer prepares the other end of the hairpin in much the same way as Drosha and releases the mature miRNA which is then ready to recognise its mRNA target and act upon it.

Plant miRNAs are specific: their sequences match their complementary RNA targets with great precision. Animal miRNAs are far more promiscuous. The match is far less demanding and, as a result, one miRNA will bind to as many as one hundred different target sequences. From Nature’s point of view, it may sound economical but it just makes things difficult in the laboratory. It is a relatively easy task to identify a specific miRNA within a specific pathway if the said miRNA only has one target. However, in reality, one particular miRNA regulates many different genes and is thus most probably involved in as many cellular pathways.

The fact that animal miRNAs are so dissolute makes it difficult to use them as diagnostic markers for disease or for exploiting them for therapeutic benefit. Nevertheless, much research is being carried out in this direction to make some sense out of the miRNA jungle. Since miRNA silencing in plants is far more straightforward, a number of applications have already been made. The very first was with on tomatoes where an engineered miRNA was used to prevent the expression of an enzyme which participated in the softening of the cell walls once ripe. Ripe tomatoes could then be harvested without falling apart. Such practises cannot be widely used though because of our whims of genetically modified crops.

An obvious question is why do miRNAs exist? Do they provide some special regulatory property that transcription factors do not? Is the silence Drosha and Dicer create of a different nature to that of the well known transcription factors? Time will tell. Nature continues to show that she has many facets and those she nurtures are usually there for a reason…

Antlers are not an uncommon sight these days. If you are lucky enough to live on the outskirts of a forest, there is a great chance that you will spy an antler or two, usually at dusk. Antlers are made out of bone. They grow from pedicles that form at puberty and which, in time, become permanent protuberances from where antlers bud and are cast seasonally. They can grow at the amazing rate of two centimetres a day and represent the only example of both irrigated and innervated cartilage in the animal kingdom.

Once antlers are cast, the next generation initiates immediately thanks to resident stem cells on the permanent pedicles. These cells differentiate first into chondroblasts and then into chondrocytes, which are associated with the formation of cartilage. Mineral deposition then occurs on the cartilage scaffolding, and bone is formed. This stage gradually gets rid of any blood supply which is made to the antlers. As a consequence, they stop growing and their metamorphosis to bone is completed. The final touch comes with the shedding of a thin film of velvet skin that coats the appendages, and the antlers are then ready for the rutting season.

Red Stag, from an original painting by Robert E. Fuller

Courtesy of the artist

Naturally, the regeneration of an organ demands the existence of a complex network of proteins. Annexin 2 is just one of these proteins but an essential one, since it seems to be directly involved in bone formation. More specifically, annexin 2 seems to be involved in the formation of calcium channels and mineralisation in the environment of chondrocytes and osteoblasts. Annexin 2 is also involved in many other mechanisms and it is now becoming obvious that it is a multifunctional protein. It assembles into a heterotetramer and belongs to the very large annexin family which is characterised by the existence, in their sequence, of an annexin domain – a 70 amino acid domain – of which each type of annexin has a defined number. This particular domain binds calcium – a feature characteristic to all annexins.

Annexins are distributed both in the animal and the plant kingdom; from humans to guinea pigs, frogs, flies, zebra fish, worms, moulds and mouse-ear cress. They are found in many different tissues and participate in a variety of physiological processes. All are calcium-dependent and bind to phospholipids, and are usually found in the periphery of the plasma membrane, either intracellular or extracellular. One form even seems to be not only extracellular but also soluble. This was a surprising discovery because annexins do not have a signal peptide, so they must follow a route other than the customary endoplasmic reticulum secretory pathway prior to secretion.

Besides antler formation, annexin 2 is involved in a host of other processes such as fibrinolysis, cell proliferation and differentiation as in bone formation, endo- and exocytosis, cell migration, cell shape and even immunity. As a consequence, it is expressed in many different tissue types such as the central nervous system, the cardiovascular system, bone marrow and the small intestine. In fact, annexin 2's tissue and function versatility is at the origin of an equally versatile nomenclature – as is frequently the case. And, with the years, it has been given a variety of names such as p39, calpactin I heavy chain, protein I, chromobindin 8 and lipocortin 2…

When a protein is multifunctional in this way, there is a big chance that it is involved in just as many diseases. So far, annexin 2 is known to be over-expressed in patients suffering from acute promyelocytic leukemia, which results in excessive fibrinolysis. On the brighter side of things, annexin 2’s involvement in fibrinolysis could be promising for the design of anti-coagulant drugs for those suffering from cardiovascular complications. Furthermore, though it is not clear why, annexin 2 also seems to have a suppressive effect on tumour malignancy – which is an excellent reason to get to know it better, although it is always a delicate thing to associate any protein with an anti-tumour effect when the said protein is blessed with so many functions.

Movement or not, some people seem to stay lean whatever their calorie intake. This could be because they are the carriers of a ‘fidget’ gene, which makes them shuffle and shift more than necessary – as far as energy balance goes. Bsx – or Brain specific homeobox – is the fidget gene. Mice that carry the wild type version were recently shown to be ten times more active than those who carry the mutated form. As a consequence, in an environment where food is plentiful, the laid back mice will tend to stock fat whereas their more active counterparts will keep trim. So far, nothing new. We are all aware that a lack of exercise is not ever going to help you lose weight. But if you take it one step further, what would be the point of a protein that is there to make you move with regard to energy homeostasis?

Such proteins are likely to be the product of a proposed complex gene network, known as the thrift gene network. The thrift gene theory made its first appearance in the 1960s. It hypothesizes that animals carry a set of genes where the act of overfeeding coincides with food abundance, and stocks are made with the future prospect of famine. In our day and age though, there is so little famine in some parts of the world that, in many instances, there is a lot of overeating. Subsequently, many people are overweight. The thrift gene theory is an elegant attempt to explain obesity which is spreading worldwide. However, like all theories, it has met with some distaste and a number of scientists have suggested that being overweight is less a question of fat collected in the event of future starvation, than humans who are less faced – if not at all – with problems linked to predation, which are not only the source of stress but also get you moving.

Old Woman Eating Peas, Jeannette Langmead

Courtesy of the author

It remains that Bsx certainly seems to be a protein involved both in locomotion and food intake. It is one of over a hundred homeoproteins isolated in mice. They are transcription factors and Bsx, in particular, is largely expressed in the hypothalamus, the part of the brain involved in many important activities, including appetite, or the lack of it. Furthermore, Bsx not only seems to be important for the correct development of the embryonic brain as well as its adult function, but is also involved in the formation and maintenance of the mammary glands.

The hypothalamus organises two major networks of neurons, one of which encloses the NPY/AgRP hypothalamic neurons which regulate feeding behaviour and body weight. Bsx is not only expressed in NPY/AgRP neurons but is also required for their expression. As a consequence, Bsx not only affects the hypothalamus itself but also distant target organs – such as the mammary glands, for instance. So far, Bsx has been found in vertebrates as diverse as humans, mice, chicken, zebrafish and frogs. Hence, it is a little surprising to discover that Bsx has a role in mammary gland formation. This implies that, over time, the protein has acquired an additional function in mammals. A function still linked to food, nevertheless…

Involved in the molecular regulation of not only feeding but also locomotion, Bsx protein proves to be at the heart of an exceptional behavioural response: one related to food and movement. Without it, calorie intake is upset, leading to weight problems. This could prove to be a drug target for future therapies that would help people who suffer from obesity, for example, which is the source of health problems that kill millions of people every year. Once again, Bsx cannot be held as the sole culprit. Weight imbalances are always due to labyrinthine molecular networks and, obviously, the environment plays a role too. Nevertheless, Bsx could prove to be a novel and precious drug target to help people shed fat.

Cover illustration for "journey into a tiny world"

© Vivienne Baillie Gerritsen, Sylvie Déthiollaz

Although this article celebrates the publication of the English version of “journey into a tiny world”, the original version – Globine et Poïétine sur la piste de la moelle rouge – was written in French five years ago. Once the idea of a story had been agreed upon, the next step was to decide what we were going to write about, and then write it. The tale had to involve proteins; that was our only dictum. The rest was up to us.

The idea of a journey into the recesses of a little girl’s body arose quite naturally. However, there had to be a reason for such a journey. One that made sense. It wasn’t long before we imagined that the little girl had to take medicine – a protein – that would lose its way inside her and, in so doing, get the chance to visit numerous parts of her body as well as meet other proteins. Our hope was that children would discover that an organism is full of different kinds of protein, which each have a specific job to do. Sylvie had just finished an article on EPO (erythropoietin), a protein which has the capacity to stimulate the production of red blood cells in the bone marrow. This became our starting point.

Little did we realise though that the choice of something so specific would put certain restrictions on our imagination… For one, EPO could not be swallowed but only taken by injection. Secondly, several weeks into the creation of our tale, Sylvie announced that the little girl was far more seriously ill than we had imagined! It didn’t change the course of our story though… And Sylvie and I moulded our characters, weaving them in and out of situations according to our fancy. It was a delightful experience.

You may wonder how two people can write together. There is no rule to how this can be done. But as far as the making of this tale goes, I wrote from my kitchen, while Sylvie wrote from the office. We wrote up the different chapters independently and then compared them. To our constant astonishment, our minds glided along the same paths and most of the time we were thinking along the same lines, which made things relatively easy. Sylvie then sifted and sorted the ideas and adventures of our molecules, keeping the best parts and discarding the poor ones. As a result, within a couple of months, we managed to produce the French version of the tale.

“Globine et Poïétine sur la piste de le moelle rouge” was the title. It is the story of Poietin who careers around a little girl’s body – Lily – with Globin, a friend she picks up on the way. Together, they experience great adventures discovering what it is to look through an eye, to sit on the edge of a wound or to watch a heart beat, while meeting other proteins like Actin, Myosin, Orexin or Insulin. Following a sequence of exploits, Poietin finally finds the bone marrow she needs, from where she will be able to stimulate blood cell production and save Lily’s life.

During the science fair, a modest set with two red armchairs, a carpet and a white canvas mounted on an easel – on which we projected the illustrations which are now part of the published book – was arranged in a far corner of one of the villa’s drawing rooms. We would have liked a local artist to do the illustrations for us. When we were told how much it would cost, it became obvious that we would have to rely on our own artistic talents. So Sylvie and I grabbed a pencil and a paintbrush and produced our interpretations of the various characters you can find strewn through the book. Despite a solid background in biology and, consequently, a sound understanding that proteins have no eyes, mouths, arms or feet, we decided that if we wanted to give them some kind of a literary life, this was one of the ways to go about it.

The tale was read several times over a weekend by two actors who managed to infuse life, beauty and magic into the story. And we will always remember the little girl who stayed to listen to more than one reading and who, by the end of the day, had learned some of the lines off by heart. Meanwhile, she had managed to drive her mother – whose only wish was to head back home – round the bend. The whole thing turned out to be a success, and a number of parents asked us whether we were thinking of making a book out of Globin’s and Poietin’s adventures. We thought it was a good idea, and the book was published in French in July 2003. And four years later, the time and energy was found to translate the tale into English.