Over time, animals developed their tasting abilities to detect the difference between bitter and sweet, in order to shun poison. Coupled with the ability to discern colour and texture such behaviour helps to keep a species alive. Including Homo sapiens. The human taste for sugar – and its addition to foods and beverages – seems to stretch as far back as prehistoric times where sugar cane plantations are known to have been grown in Asia. The expensive refined sugar made its way to Europe in the Middle Ages only and, much like the advent of cocoa centuries later, was introduced into the upper class circles as a delicacy. By the 18th century, however, sugar was being refined from the less expensive sugar beet and a taste for things sweet slowly spread to all social classes.

Sucrose was soon within everyone’s economic reach, gradually paving the way to health problems that are currently ravaging many developed societies. Sucrose substitutes - in particular Saccharine – had already appeared on the market as early as 1879. However, this was less for health reasons than to make sweetness accessible to those who had little means; Saccharine was also known as the poor man’s sugar. Ever since, the quest for artificial sweeteners has never ceased and everyone is acquainted with names such as Assugrin and Aspartame. So why is yet another sweetener, i.e. hernandulcin, of so much interest? Many artificial sweeteners are ten times or hundreds of times sweeter than refined sugar. Hernandulcin, however, is one thousand times sweeter – a godsend for the industry.

Lippia dulcis, by Surething

source: wikipedia

Hernandulcin – named after the man who brought it back to Europe – is an essential oil found in a plant known as Lippia dulcis, or Aztec sweet herb. Lippia dulcis grows extensively in tropical America and can be found on the markets where it is sold not only for its sweetness but also for its abortifacient and infertility qualities – which may be the result of some of its toxic substances, such as camphor. Though the plant was first described by the Spanish physician Francisco Hernández de Toledo in the 16th century – following the first scientific trip ever made to South America by the Spaniards – its properties were only rediscovered in the 1980s following research carried out on ancient botanical literature. There are many types of Lippia that are used to treat all sorts of afflictions ranging from indigestion, hepatic diseases and cutaneous disease, to burns, wounds and menstrual disorders. Certain sorts are also used as sedatives, stimulants and insect repellants while others are used for food seasoning and beverage flavouring. In Cuba, the juice of Lippia is used to dye cigarette paper.

Hernandulcin is extracted from the leaves of Lippia dulcis, in the form of an essential volatile oil. Besides its natural sweetening properties, it is also sold in South America as a herbal remedy for coughs, bronchitis, urinary retention and inflammation! From a chemical point of view, hernandulcin is part of the very large family of terpenoids – which are known to have many different properties and are widely used for flavouring, in cosmetics, as fuel substitutes and in all sorts of medicines. Among the terpenoids, hernandulcin is a sesquiterpene ketone, whose backbone is (+)-epi-alpha-bisbolol. Though scientists still do not know which terpene synthase actually synthesizes hernandulcin, they have managed to isolate the enzyme responsible for the synthesis of (+)-epi-alpha-bisbolol, which they have prosaically baptised: (+)-epi-alpha-bisbolol synthase. In fact, four forms of epi-alpha-bisbolol were characterised; three of which, however, had either a bitter or pungent taste.

In the realm of sweetness, terpenoids have been used for many years now to replace the old-fashioned refined sugar from cane or beet, whose sucrose side effects – when absorbed exaggeratedly – can be very harmful. Obesity is the major one; a condition which haunts our societies and lays the foundations for serious afflictions such as heart disease and diabetes. Sugared foods and beverages have become the basis of most of the world’s diets nowadays, to the extent that millions of people cannot imagine doing without and are usually unaware of the amounts they swallow on a daily basis. This is why it is so important to find sugars that are less harmful to human health – such as those based on terpenoids. Hernandulcin is ideal in that it is not only a powerful harmless sweetener but, so far, has also proved to be non-carcinogenic.

Scientists have rediscovered a seemingly harmless hernandulcin and found the synthase that is the designer of its backbone. So now what? Bacteria can be engineered for the large scale production of (+)-epi-alpha-bisbolol and, ultimately, the low calorie sweetener hernandulcin. But this last step still requires the intervention of yet another synthase – which remains to be brought to light… For the sake of global human health and all instances related to it, being able to provide a powerful sweetener that has none of the drawbacks that sucrose involves is great. However, would it not be a good thing to start promoting tastes that are not so sweet, by adding less sugar – whatever its nature – to food and drink, instead of continuing to encourage a sweet tooth?

One of the earliest descriptions of autism involves a certain Hugh Blair of Borgue, an 18th century Scottish landowner, whose marriage was annulled by his brother on the grounds of a woman seeking to take advantage of psychic fragility. Her motives were apparently less for reasons of love than the prospect of gaining her spouse’s inheritance. The term ‘autism’ was coined in 1910 by the Swiss psychiatrist Eugen Bleuler whilst defining symptoms linked to schizophrenia, and the word was chosen to describe the morbid self-absorption his patients showed. It was only in the early 1940s that the word ‘autism’ began to appear in the realm of child psychopathologies and, in the 1960s, the condition was established as a syndrome per se and distinct from various forms of schizophrenia, for example.

In the mid-1970s, things were taken further and it became apparent that autistic behaviour had a genetic origin. Today, researchers believe that mutations are in fact the affliction’s main cause, and autism is likely to be caused by not only one mutation but many, situated on different genes, the combination of which gives rise to autistic behaviour. This could explain why there are so many different forms of autism. And also the reason some forms appear to be unique.

Look at me, by Beth Hanson (USA)

founder of Autism Art Project

courtesy of the artist

Autism related to the BCKDK (or branched-chain alpha-ketoacid dehydrogenase kinase) enzyme is rare and hereditary and, so far, has only been described in eastern European families where consanguine marriages are frequent. BCKDK is a kinase involved in stopping a larger enzyme complex, BCKDH (or branched-chain ketoacid dehydrogenase), from degrading branched amino acids – namely leucine, isoleucine and valine – that humans are unable to synthesize. The kinase does this by inactivating one of the dehydrogenase’s subunits. As a result, BCKDH activity is blocked. The branched amino acids are subsequently not destroyed and can be used in certain metabolisms such as protein synthesis for instance. BCKDK will refrain from deactivating BCKDH when the levels of these particular amino acids become toxic for the body, and thus acts as a supervisor in branched amino-acid metabolism.

But what does this have to do with autism? Autism is a case of defective information processing in the brain, itself caused by nerve cells and their synapses whose organisation and connections have been altered. How this happens, and in what way, is far from understood. And there are, no doubt, as many ways as there are forms of autism. Leucine, isoleucine and valine are found in the brain where they are involved in neurotransmission. When everything is working properly, specific transporters taxi these particular branched amino acids from the blood into the central nervous system. When BCKDK is deficient, however, transport across the blood-brain barrier is modified. The seats left free in the transporters can be taken up by other molecules – amongst which glycine and tyrosine, which also happen to be neurotransmitters but of a different nature.

This particular type of autism seems, then, to depend on the metabolism of branched amino acids and, hence, their presence, or absence, in the blood. If so, would a simple diet of leucine, isoleucine and valine be sufficient to counteract a deficiency in BCKDK? Well, it seems to be the case…in mice. Mice, in which BCKDK was rendered inactive, showed signs of a disturbed neurological system with bouts of epilepsy – precisely one of the symptoms of this particular form of autism. When the mice were given a diet of the missing branched amino acids, within a week their troubles disappeared. The same diet was fed to patients suffering from the similar form of autism – and their blood levels of leucine, isoleucine and valine did indeed increase. However, there was no observable effect on their behaviour.

Mother Nature always has the last word: life is more than just a sum of parts. However, with these tests, scientists have demonstrated that it is possible to treat a certain neurological disorder, albeit murine, by adapting an individual’s diet. Scientists currently estimate that 5 to 10% forms of autism are the result of metabolic disorders. This means that these types of autism could be treated by adapting a patient’s diet. Such a discovery also implies that tests could now be developed to diagnose metabolic autisms – of which there are no doubt many.

In the human population, the occurrence of autism is increasing. This is no doubt because doctors are able to diagnose it better. But our lifestyle may have something to do with it too. Metabolic analyses of cerebrospinal fluid in newborns, for instance, might help to unveil lurking forms of treatable or preventable forms of autism. And relieve the despair that runs through a family when a child moves into its silent world.

The notion that plants resorted to sex to flourish was first established by the German botanist and physician Rudolf Camerarius (1665-1721) who wrote, in a letter dated from 1694, that ‘no ovules of plants could ever develop into seeds from the female style and ovary without first being prepared by the pollen from the stamens, the male sexual organ of the plant’. Almost a century later, the German theologist and naturalist Christian Sprengel (1750-1816), who spent most of his life delving into the mysteries of plant sexuality, described the tricks of plant pollination – such as nectar guides and the art of mimicry in all its forms. Research on plant sexuality has evolved a lot ever since. Naturally. And today a far greater understanding of all the mechanisms plants use – both from the macromolecular and the molecular levels – are being unveiled thanks to novel technologies.

The amount of mechanisms thought up by plants to bring a male gamete closer to a female one is bewildering. And botanists have most certainly not observed them all. Plants make passive use of the wind and the fur of occasional wild animals to get their pollen to travel – in the hope that it will be deposited on a plant of the same species. Birds are used in the same way and pollen grains can be transported over huge distances. Plants have also learned how to lure insects into their flowers to pick up their pollen – by using cues such as colour, odour, scent and shape. Temptation can even come in the very subtle form of insect sex pheromone mimicry*, where plants become hyper selective and direct their lures towards a certain species of insect – thereby ensuring that it will deposit the pollen onto the same species of plant.

Malaria, painting by Fania Simon (USA / West Africa)

courtesy of the artist

All these techniques, however, are for the initial phase of ‘gamete approach’. Once a grain of pollen has been deposited on a flower, the next step is for the male gamete – harboured within the pollen grain – to reach the female gamete. So the grain germinates – as long as the surrounding conditions are appropriate. A bulge appears on the surface, and gradually becomes a tube – the pollen tube – which elongates. Inside this tube is found the male gamete (or in the case of Arabidopsis and all angiosperms, two male gametes, one of which will fertilize the ovule). When it meets the ovule, the end of the pollen tube ‘explodes’ and one of the gametes will fuse with the ovule. An arrangement which is not all that far removed from the human reproductive system when you think about it.

The whole system is complex. There are hosts of molecules at work for all the different stages. Namely, germination, pollen tube elongation, what could be termed ‘botanical ejaculation’ and gamete fusion. Protein HAP2 has a role both in pollen tube guidance – not elongation – and gamete fusion. Indeed, mutant hap2 has no effect on pollen tube growth but the wild type HAP2 is necessary for the tube to elongate in the right direction, i.e. in the vicinity of the ovule. This particular talent may be a sort of ‘quality control’ mechanism; if the sperm is of poor quality, pollen tube guidance is faulty, and the gamete never reaches the ovule. Thus demonstrating an active role for sperm cells in the process of fertilization; a notion that is gathering momentum within the world of research.

HAP2 is hence needed both for pollen tube guidance and gamete fusion. The protein is largely expressed in pollen grains about to undergo germination, and is found in the plasma membranes of the sperm cells and in the sperm cell cytoplasm, lodged in the endoplasmic reticulum membrane. How does HAP2 help to guide the pollen tube towards the ovule? The N-terminal tip of the plasma membrane protein is in direct contact with the pollen tube cell’s cytoplasm – perhaps even with the cell’s cytoskeleton – and consequently well positioned to influence tube direction. The sperm cells also migrate towards the tip of the pollen tube by way of the cell’s cytoskeleton. When the tube bursts, it releases the sperm, and HAP2 participates in gamete fusion – in fact, HAP2 is the first known gene to have a direct function in plant reproduction.

A surprising fact: HAP2 seems to exist in many eukaryotes, but not in higher animals. This would imply that the system is deep-rooted and that a different system evolved in higher animals – perhaps more sophisticated, more adapted to their needs. In particular, HAP2 is found in the mammalian parasite Plasmodium – the organism that transmits malaria – and is believed to be involved in gamete fusion, which occurs in the gut of the female mosquito once she has sucked up the blood of a victim, and before she finds another… One way of trying to block Plasmodium transmission to a human, and contributing to the eradication of malaria, would be by finding a vaccine that is able to deactivate HAP2, thus preventing Plasmodium reproduction. This brings hope to an illness which – according to WHO’s latest estimates – afflicted almost 220 million people in 2010 and killed about 660,000.

Orchids have been popular for a long time. Besides their looks, they provide us with the widely favoured vanilla that is used in cuisine all over the world. But good looks are not enough for perpetuation. Orchids – like many plants – have thought up shelters, scents and even food to attract potential pollinators. And pheromones: the ultimate artifice. Luring pollinators by using pheromone cues has been coined ‘sexual deception’ and was first described at the dawn of the 20th century in the orchid genus Ophrys. In fact, in the Euro-Mediterranean region, pollination by sexual deception is considered to be this particular type of orchid’s hallmark. In a nutshell, males of a certain species of wasp are led to the Ophrys orchid, blind to the fact that it is not another wasp. Having reached a part of the flower known as the labellum, the wasp proceeds to copulate and then takes leave with its furry coating surreptitiously covered in pollen. Turned on by yet another Ophrys, the wasp deposits the pollen onto its flower. And so on. Scientists argue that while the shape and texture of the labellum certainly plays a role in luring pollinators, the pheromone mimic is far more powerful.

Mimicking a pheromone is no simple task. It means that the plant has gone to the extent of cracking the chemistry that underlies the female sex pheromones in wasps, for instance, and then twisting its own metabolic pathways to mimic it. The sex pheromones of female wasps are a mixture of cuticular hydrocarbons, the most important of which are alkenes and the location of double bonds within them. Different sex pheromones present double bonds at different locations. Different Ophrys orchids actually produce a pheromone parody of a specific female wasp’s sex pheromone, thus ensuring that the same species of wasp will keep coming back but, more importantly, will also deliver the pollen to the right flower. Over the years, such manoeuvres have probably had an effect on orchid evolution and scientists argue that orchid speciation may well be a consequence of pollinator adaptation.

Paphiopediulm sukhakulii, painting by Robin Street-Morris (USA)

courtesy of the artist

Alkenes accumulate in the labella of Ophrys flowers – a protrusion which serves, literally, as a landing platform for pollinators. Stearoly-acyl carrier protein desaturase (SAD) is the name of the enzyme involved in plant alkene biosynthesis of which there are various isoforms. In certain types of orchids, namely Ophrys sphegodes (early spider orchid), SAD2 seems to the active one. At the beginning of alkene biosynthesis, SAD2 inserts a double bond into a saturated fatty acid to produce an unsaturated fatty acid. This ultimately leads to the production of alkenes. The location of the double bond is important for the type of sex pheromone produced. Alkenes with different double-bond locations define the kind of pollinator that will be seduced. Consequently, the genes which specify double-bond positions may well be directly associated with pollinator adaptation. An intriguing thought. Likewise, all you need is a change in SAD activity – namely in the binding pocket which creates and locates the double bonds – for a change in alkene specificity, and hence pheromone specificity. What is astonishing is that, at the sequence level, plant SADs are unrelated to their animal counterparts! Which makes the orchid pheromone fraud even more devious.

A question which arises: why specialise pollination to such an extent? Would it not be wiser to let a greater variety of insects pollinate the same species of plant? Would that not perpetuate the species in a more effective way? Even if a tad wastefully? It has all been thought out. If an orchid produces a sex pheromone meant for only one type of wasp, then the said wasp is sure to be seduced by an orchid of the same species. What is more, every orchid releases an astounding 12’000 grains – so progeny are ensured. Although only about 10% of the Ophrys population is actually pollinated, it is enough to preserve the population. As a rule, there is no real guarantee that an insect covered in pollen will actually deliver it to the right flower. So the Ophrys conspiracy is very subtle. Scientists have discovered that when a plant decides to specialise with one pollinator and, what is more, lures it in with a promise of sexual intercourse – the pollinator goes from one orchid flower to another with little pollen loss in the transport process. Such a tight selection on plant traits is believed to be a major driving force in flower diversification and speciation.

But things are even more complex and cunning on behalf of the Ophrys orchids. Only the male wasps are attracted to the flower’s labellum. Now female wasps produce male wasps without the help of their men. They only need male wasps to produce female wasps… From an orchid’s point of view, it knows that, whatever happens, there will be plenty of pollinators around. But it is also a risk. All in all, here is an extreme example of a plant that has learned how to trick an insect so subtly that the plant has become wholly dependent on it for its survival. Talk about walking on thin ice. Yet sexual deception has evolved several times in different types of orchid, so it must be successful. And the orchids seem to have been very thoughtful too in their plight; the male wasps obviously make the most of their flings and leave a little ejaculate behind them. And, though they ignore their real mates, the ladies are still able to reproduce.

watercolour, by Amélie Frison (Switzerland)

courtesy of the artist

One thousand, every heartbeat. That is the rate at which sperm multiply in a healthy human male individual the moment puberty kicks off. It is a lot. And each sperm is potentially fertile. Ejaculation is therefore a very serious affair, and pushes one lonely egg into dangerous terrain if pregnancy is not desired. This is where contraceptives come in. Contraceptives for men – other than condoms and vasectomy – remain a tricky affair for a number of reasons. One being the sheer amount of sperm a contraceptive has to consider. Finding a solution at the level of the egg seems – naturally – less of a hassle than looking for something able to deal with millions of sperm at a time. Which is no doubt one of the reasons – though by far not the sole reason – that the popular pill came crashing into our society in the 1960s. Fifty years later, there is hope that a male contraceptive has been found. It all has to do with a protein known as Bromodomain testis-specific protein and a small inhibitor molecule known as JQ1.

Contraception – male or female – is nothing new. In fact, it has been around ever since it became clear that what men put into women was capable of making a baby. The Ancient Greeks would have been the first to put two and two together. From then on, all sorts of potions were devised to counter fertilisation. In the Ebers Papyrus, an Egyptian medical papyrus dating back to 1550 BC, women are told how to make a paste out of dates, acacia and honey, which they can then spread onto wool and use as a pessary. All sorts of herbs were also used: the contraceptive property of hemp seeds (Cannabis sativa) and rue (Ruta graveolens) were described in early medical writings in 40AD for instance. And many more followed, in many different societies.

The use of condoms, interestingly, may well have stemmed more from a way to prevent sexually transmitted diseases than to avoid pregnancy. Though some historians and archaeologists argue that loincloths were used in Ancient civilisations, it is only in the 16th century that there is an unquestionable description of condoms used to prevent the spread of syphilis. These consisted of dry linen sheaths that had been soaked in a chemical solution and were attached to the end of the penis by way of a ribbon.

None of these methods though have ever proved to be 100% birth proof. It was only with the advent of the pill in the very early 1960s that an effective and simple method seemed to have been found – though it does mean tampering with a woman’s menstrual cycle. Besides vasectomy, which can only really be performed on men who do not wish to conceive at all anymore, there has been no marketable male contraceptive. Most fairly recent trials have involved meddling with the male hormone testosterone, which work reasonably well, but have never made it to the chemist’s counter. So the Bromodomain testis-specific (BRDT) protein and JQ1 come as a refreshing prospect in the world of birth control. Indeed, the BRDT-JQ1 system does not interfere with any of the male hormone pathways. Instead, it acts at the very beginning of spermatogenesis and interferes with sperm development.

BRDT belongs to the large human bromodomain family. As its name suggests, its sequence presents a certain number of bromodomains. Typically, the domain is represented by a bundle of four alpha helices that forms a binding pocket which is able to recognise acetylated lysine residues such as those on the ends of histones. Acetyl-lysine recognition by BRDT is a prerequisite to the protein binding to histone H4 for instance. When this happens, the DNA/histone arrangement is remodelled, and genes involved in spermatogenesis are set off. Now if BRDT were unable to carry out its function, then sperm would not develop.

Scientists discovered that a potent thienodiazepine inhibitor known as JQ1 was able to do just this: JQ1 slips into BRDT’s acetyl-lysine binding pocket thus making it impossible for BRDT to link to H4. As a result, the genes needed for sperm cells to mature are not triggered off and spermatogenesis is impeded. When JQ1 was injected into mice, the sperm number and motility were very much reduced, and there seemed to be no effect whatsoever on the male hormone pathways. JQ1 seems to act upon BRDT only. Even better, when JQ1 therapy is withdrawn, males recover all their reproductive capacities.

Though mice and men are worlds apart, the good news is that the bromodomains of their BRDT proteins are almost identical. Consequently, scientists believe that there is a great chance that JQ1 should work as an effective contraceptive in men too. It is not the first time that scientists have announced ground-breaking news in this field. But it is the first time that they have found a contraceptive that does not involve male hormones. However, it will still take a few years to find out if there are any long-term side effects, such as developmental malformations in progeny, besides finding a way of taking the contraceptive orally rather than by injection. Contraception has been on the minds of humans for a long time, for many good reasons. An undesired pregnancy entails an awful lot – both in Western societies but also in third world countries. If scientists can develop contraceptives that are not only affordable but also acceptable in societies other than our own, it can only be a giant leap for civilisation.

What distinguishes humans most, from all other species, is our brain and what it is capable of doing. Tracking down anything which would have had a direct contribution in designing the human brain will help us understand how it all happened. This is why scientists spend a lot of time looking for the genes and events which fashioned such an extraordinary and intricate organ, as they track down those that are part of abilities specific to humans – for example FOXP2, without which our faculty of speech would be impeded. It is a known fact in evolutionary geneticists’ circles that mutations such as the duplication of genes provide excellent substrates on which time and natural selection can tango when it comes to human brain development.

There are in fact four versions of the SRGAP2 gene in humans – SRGAP2A, B, C and D – all found on the same chromosome and the result of three subsequent duplications of the same original gene. It is thought that SRGAP2A – the original gene – was duplicated about 3.4 million years ago, giving rise to SRGAP2B. SRGAP2B was duplicated a second time about 2.5 million years ago and produced SRGAP2C. And this duplicate was duplicated yet again, about 1 million years ago and resulted in SRGAP2D. So far, it seems that there has been no further duplication. Two of these variants – the original one and SRGAP2C – have remained active, while the other two appear to have no particular function. In fact, they have suffered so many mutations over the years that they are believed to have become genetic junk.

Location 23.02.2005, acrylic ink on paper, by Susan Aldworth (UK)

courtesy of the artist & GV Art Gallery, London

The original gene – SRGAP2A – is known to have a role in brain development. It is expressed very early on in embryogenesis and all through adulthood, in the cerebellum and the neocortex which happens to be the part of the brain that controls abilities specific to humans, like language and conscious thought. In mice, SRGAP2 is involved in neuronal maturation and harnessing dendrite density. The human-specific SRGAP2C is also expressed very early on in foetal development and in the adult brain where it seems to promote quite the opposite of what SRGAP2A does, i.e. it delays neuronal maturation thus giving neurones more time to migrate and spread out dendrites.

How does SRGAP2C do this? SRGAP2C is a truncated form of the original SRGAP2A gene, yet it seems to have remained active – though not at all in the same way as the gene it originally sprouted from. SRGAP2C binds to SRGAP2A and, in doing so, stops it from carrying out its original function. As a result, neuronal maturation is arrested and the neurones, and their dendritic protrusions, can branch out further in the space that is given to them. In the past, such neuronal freedom will have given rise to more connections and hence greater ‘computational’ power. This will have also given our ancestors’ brains the means to acquire a higher level of intelligence, and supply them with the cognitive skills they needed to develop the very first tools and forms of social behaviour which have ultimately led us to where we are now.

One gene on its own cannot bring about such a fundamental biological and evolutionary event. However, it is probable that SRGAP2C had, and continues to have, an important role in human brain development. From an evolutionary point of view, researchers believe that the effects of SRGAP2C were likely to be more or less immediate and formed an almost ‘spontaneous’ breach between Australopithecus and the novel genus, Homo.

Though intelligence and the human mind have been through a most intriguing adventure, it does come with its drawbacks. The brighter a living being is, the more prone it is to psychiatric disorders. This is why it is so important to discover genes such as SRGAP2. One case of infantile epilepsy and severe psychomotor disability has indeed been tracked down to a problem within SRGAP2. And researchers suspect that some forms of autism – which show characteristic neuronal dendrite branching out – could also be due to the doings of an unsound SRGAP2. This said, research has only been carried out on mice. And for disorders such as autism, the host – in this case – is by far not the best. The making of the human brain is an exciting field of research. Though it is somewhat disquieting to realise that human intelligence was dependent on chance mutations.

Nothing is perfect. And nature is no exception. This said, we should be grateful for nature’s imperfections because, were it not for them, we would not be here. Without the changes that have been accumulating in genes over millions of years, we would not know the rich diversity of species that inhabit Earth today. Yet we all know that mutations can be lethal to an individual. Tinker with a crucial position in a gene and you can find yourself with a severe handicap. Extensive damage to a cell’s genome can lead to all sorts of ailments, not the least cancer. This is why Nature imagined DNA repair mechanisms so as to limit the damage and prevent as many mutations as possible. One such mechanism is nucleotide excision repair, and at its heart: protein Xeroderma Pigmentosum A (XPA).

Along with other proteins, XPA forms a complex that specifically recognises damaged DNA – especially alterations caused by UV light – and then severs the part which contains the lesion. Once the spoilt nucleotides have been removed, they can be replaced by sound ones, restoring the DNA and the information it should have carried in the first place. The precise role of XPA in the whole process is still misunderstood. As the protein specifically recognizes DNA whose helix has been distorted because of mutated nucleotides, it was initially thought that XPA raised the alarm over DNA damage. Such is not the case however. The actual binding of XPA might signify that the DNA is indeed damaged and prompt the assembly of the rest of the nucleotide excision repair machinery. As an illustration, XPA’s association with one of the DNA severing proteins might ensure the latter’s correct positioning and thus guarantee accurate excision of the damage.

Whatever its exact function may be, it is clear that XPA is essential for DNA repair to happen in the first place. If the protein is unable to carry out its task, the whole repair process fails leading to terrible consequences for an individual’s health. Mutations in XPA, for instance, cause the disease that gave the protein its name: Xeroderma pigmentosum. Xeroderma pigmentosum was first described more than a century ago, in 1874, by Moriz Kaposi, a professor of dermatology in Vienna. But it was only in 1968 – almost a century later! – that James Cleaver, himself a professor of dermatology in San Francisco, linked the disease symptoms to defects in DNA repair.

The Children of the Moon, by Catherine Arsaut © (Australia)

courtesy of the artist

Patients suffering from Xeroderma pigmentosum are extremely sensitive to sunlight and have to wear protective clothing as even brief exposure to UV light leads to severe sunburns. As a result, children who are affected stay indoors during most of the day and only go out at night, which is why they are sometimes known as “moon children”. It is hardly surprising then that patients suffering from Xeroderma pigmentosum are also a thousand times more at risk of developing skin cancer and, in some cases, the disease is associated with progressive neuronal degeneration...

Though XPA is essential for DNA repair, it also occupies a central position in regulating the whole process. Indeed, several mechanisms modulate the activity of nucleotide excision repair and they all do so by targeting XPA first. Take the circadian clock for example, the internal clock that adjusts the daily rhythm of many physiological processes. This particular clock affects the rate of DNA repair through its effect on XPA expression. In mouse brain, liver and skin, for instance, the level of XPA and consequently nucleotide excision repair activity varies throughout the day, with a maximum in the evening and a minimum in the morning. DNA repair can also be activated by getting XPA to move to the cell’s nucleus. This tactic is chosen once DNA damage has been sensed and cellular processes are triggered off in order to deal with any; getting XPA to visit the nucleus as fast as possible is one. Turning off nucleotide excision repair when it is not needed anymore occurs through XPA as well. Indeed, once the damage has been repaired and XPA is not engaged in the DNA repair machinery anymore, the protein is chemically modified and subsequently destroyed.

So, to cut a long story short, control XPA and you control nucleotide excision repair. Naturally, the fact has not gone unnoticed amongst researchers, especially as it has implications for cancer treatment. Chemo-therapeutic drugs are designed to induce DNA damage. Hence, the efficiency and side effects of these drugs largely depend on nucleotide excision repair, i.e. on how XPA behaves. Resistance of cancer cells to chemotherapeutic drugs has been linked to XPA protein levels. Depleting XPA increases the cells sensitivity to the drugs. Researchers have identified regulators of XPA expression. Clinically silencing them would reduce XPA expression and hence improve the efficiency of chemotherapeutic drugs. Another current line of study is focusing on XPA transport to the nucleus. The mechanisms controlling this nuclear transport happen to be different in cancer cells because of a mutation in what is known as the p53 gene. Targeting the mechanism specific to p53 mutant cells could prevent XPA from entering the nucleus in cancer cells. As a result, DNA repair would not occur and the cancer cells would be more sensitive to chemotherapeutic drugs – hopefully with little or no consequence to healthy cells.

Over time, Nature has set up mechanisms to counter its imperfections. Scientists are setting up their own to counter diseases by understanding Nature’s flaws in the first place. Gaining knowledge, on the molecular level, of mechanisms as intricate as DNA repair will provide the means to tamper with these processes in the hope of fixing the flaws Nature has overlooked.

There are many ways of dealing with polyspermy. Different animals use different methods; some even use more than one. Take the sea urchin for instance. Sea urchins use two types of polyspermy block: electrical and mechanical. Initially, the oocyte is charged negatively and the sperm positively – thus creating favourable ground for gamete fusion. However, upon fertilisation, the sea urchin oocyte becomes positively charged causing other eager sperm to bounce off it. This change in the electrical state of the oocyte is almost instantaneous. An additional mechanical change occurs later, whereby the zona pellucida surrounding the oocyte’s membrane changes structure and becomes impenetrable to sperm – a system used by mammals too. Mice use three post fertilisation blocks: one which prevents a second sperm from fusing with the oocyte’s membrane, a second which stops sperm from penetrating the zona pellucida, and yet a third which stops sperm from actually binding to the zona pellucida in the first place. What is more, besides these forms of polyspermy block, many organisms reduce the number of sperm further upstream in the process, as the gametes make their convoluted way to the oocyte.

In mice, the nature of the zona pellucida changes swiftly following fertilisation, making it impossible for any additional sperm to penetrate it – though many get trapped in it. It is a fact that has been known for many years but scientists didn’t know what was happening on the molecular level. Until they discovered ovastacin. Ovastacin is a proteolytic enzyme which belongs to the astacin family of metalloproteases, and is found predominantly in ovaries. Proteolytic enzymes are of huge importance since they are at the basis of all sorts of molecular regulation – and are therefore involved in instances such as cell cycle progression, tissue morphogenesis, cell proliferation, ovulation and apoptosis to name a few. In short, proteolytic enzymes are paramount in keeping an organism alive and kicking. Processed in the Golgi apparatus during oogenesis, ovastacin is stored in cortical granules. Upon sperm-oocyte fusion, hundreds of cortical granules float to the oocyte inner membrane, where they fuse and spill out their contents – amongst them ovastacin – into the zona pellucida.

Sperm and ovum, by Holly Roberts (USA)

artist's blog

courtesy of the artist

The zona pellucida is a protective sheath which surrounds the surface of the oocyte. It is composed mainly of three glycoproteins – ZP1, ZP2 and ZP3 – that form a sort of scaffold through which the sperm have to travel in order to reach the oocyte’s plasma membrane. If a sperm manages to cross the entire zone, it then fuses to the oocyte per se and releases its nucleus into the egg’s cytoplasm. Meanwhile, to scare off the fusion of a second sperm, the contents of the cortical granules are released into the zona pellucida and set about modifying its overall structure. In doing so, they are actually erecting a barrier to polyspermy. Ovastacin is directly involved in this transformation. How? Before fertilisation, sperm are attracted to the oocyte’s surface and bind to the zona pellucida by way of ZP2. Immediately following fertilisation, ovastacin is released and cleaves ZP2, thereby demolishing the means for additional sperm to dock to the zona pellucida.

Surprisingly, besides being involved in the process of post fertilisation and polyspermy block, ovastacin also has a role in promoting gamete fusion. Indeed, oocyte membrane-bound ovastacin – also known as SAS1B for Sperm Acrosomal SLLP1 Binding – is thought to bind tightly to SLLP1 which is found on the sperm’s acrosome thus bringing the two gametes even closer. So far, SAS1B (or ovastacin) seems to be the only oocyte metalloproteinase which is known to be directly involved in sperm-oocyte fusion.

Anything which affects the binding of sperm to an oocyte’s zona pellucida, or indeed its plasma membrane, is of huge interest to those carrying out research in the field of infertility studies. The more scientists are in the know of what is happening on the molecular level of fertilisation, the more they can tackle aspects of procreation and imagine novel means of contraception. Ovastacin may prove to be a good candidate. For instance, inhibiting ovastacin activity altogether could turn out to be an effective contraceptive. The metalloprotease could also prove to be relevant within the scope of fertility tests. As an example, the precocious release of ovastacin could cause premature cleavage of ZP2. The mouse model is indeed an excellent model to design contraceptive strategies. However, there is still a long way to go. And mice are not men… This said, when one realises the many opportunities there are for a sperm and an egg to miss each other, it is a wonder an encounter ever happens at all.

A snake’s venom is saliva that has become specialised in being nasty to anyone or anything that has the misfortune of being injected with it. It is synthesized in venom glands and then inoculated into the snake’s victims through its fangs, which have been designed so as to sink with ease into the flesh of a predator or prey. Snake venom is a potion with many powers – it can make blood coagulate, damage veins, interfere with a heartbeat, modify membrane permeability, cause numbness, paralysis, and even death. And these many powers are the fruit of as many different chemical entities, most of which are proteins.

Charles Lucien Bonaparte (1803-1857) – one of Napoleon Bonaparte’s many nephews and a biologist in his time – was the first to observe that venom was mainly proteinaceous in nature. Since then, many toxins – of all sorts – have been characterised. Amongst which the neurotoxins, i.e. toxins which have an effect on neurons and are able to cause insults such as mental retardation, memory impairment, epilepsy, paralysis or dementia to name a few.

Son Snake, by Amelia Hirschauer (Australia)

courtesy of the artist

This said, though neurotoxins can be very detrimental to those who receive them, they are a precious source for researchers who seek to understand how the central and the peripheral nervous systems work. And, when you get an understanding of how part of such complex networks behave, you can then attempt to design drugs which can counter instances such as memory loss, limb paralysis …and pain.

Indeed, pain is what the neurotoxin MitTx has to offer. This particular neurotoxin is part of the Texas coral snake’s venom (Micrurus tener tener) whose fangs offer intense and continuous pain by injecting poison which is able to excite a group of sensory neurons. MitTx is a heteromeric complex of two subunits: Neurotoxin MitTx-alpha and Phospholipase A2 homolog Tx-beta. And though the alpha subunit carries the neurotoxin qualifier, it is unable to carry out its neurotoxin function without its fellow beta subunit – and vice versa.

Though very little is known about MitTx and how exactly it affects sensory neurons, it has offered scientists new insights into the sensation of pain and the, as yet, unknown role of acid-sensing ion channels (ASICs) in being part of it. Indeed, MitTx seems to bind to the extracellular part of ASICs, thus causing an immediate boost in cellular calcium. How this neuronal depolarization occurs remains a mystery but it may have something to do with the lipid-binding trait of the beta subunit. What is more, depolarization is not only potent but also very long – which echoes the potency and prolongation of the sensation of pain.

It is thought that the strength of the pain may have something to do with the affinity of the alpha/beta complex, and not with the actual bonding of the neurotoxin to the channel. Much remains to be understood though. ASCIs are not unknown to the effects of toxin – tarantulas, for instance, produce toxins that target ASCIs. However, these toxins lock the channels in a desensitised state: which is exactly the opposite of what MitTx does!

Whatever the mechanism, MitTx and ASCIs provide novel insights into the world of nociception. Toxins will always be a mine of information for understanding the ins and outs of pain since Nature will always aim for the centres that produce it. And the bigger the pain, the greater the response. Conversely, scientists will be able to refine their research and design drugs that are more and more subtle for alleviating all sorts of pain, caused by all sorts of ailments. Save perhaps the pain inflicted by words.

We live in a day and age when we are told to live our life to the full. Meaning, for many, the less you sleep, the better off you are and the more you can get out of life. But is little sleep good for us? The medical profession tells us that 7 hours a night is about the optimal amount of time for a human to shut down and refuel. Yet we all know that some people can do with far less while others need substantially more. So what does it come down to? There are some sleeping behaviours that seem to run in families, which would suggest a genetic component. Sleep, however, is something particularly difficult to measure. It is made up of three ingredients: quality, duration and timing. Each of these ingredients is dependent on the season, latitude and geographical location, but also on a person’s environment, their social occupation, their biological rhythm, gender, age, psychiatric disposition and so on.

With this in mind, a few scientists took it upon themselves to find out whether a person’s tendency to sleep long hours or not has a genetic basis. To do this, they examined a cohort of over 4’000 individuals, from seven different European populations whose close ancestors were also of European extraction. For the study, none of the individuals had performed any shift-work in the past three months. None of them took any form of medication which could influence their sleeping behaviour in any way and alarm clocks were not allowed on days off work. The scientists then performed genome wide association studies and came up with one gene – known as ABCC9 – a certain variant of which was found in people who were happy to sleep fewer hours than their peers. For confirmation, they turned to Drosophila and knocked out its homologue: and the fruit flies slept less! This was proof that not only the gene has a direct role in sleeping behaviour but that it must also be quite important since it has been around for a pretty long time.

Reprise, by Eric Zener

courtesy of the artist

In mammals, ABCC9 is found in many tissues, amongst which the heart, skeletal muscle, the brain and the pancreas. ABCC9 is not a stranger to the medical profession. It has been known for some time now to have a role in smooth muscle tonality and is involved in diabetes, heart disease and certain psychiatric disorders. It so happens that these afflictions are also accompanied by sleep irregularities. Which makes ABCC9 and the discovery of its probable involvement in sleeping behaviour a very attractive gene indeed. This would suggest that certain metabolic pathways – such as glucose uptake or vascular tone regulation in smooth muscle, for instance – are linked to the phenomenon of sleep. _subscript

But what is ABCC9? ABCC9, also known as Sulfonylurea receptor 2 (SUR2), is one of the subunits that is part of an octameric potassium channel complex fuelled by ATP (K_ATP channel). K_ATP channels are transmembrane, and are found in cell or mitochondrial membranes. They are made up of two different parts: the pore and the part which regulates the whole system. ABCC9 is the subunit which has the regulatory role. There are four regulatory subunits in a K_ATP channel and four pore subunits. ABCC9 sports no less than17 transmembrane domains and is able to bind to ATP. In fact, ABCC9 acts as an ATP sensor. If the surrounding ATP is depleted, there is none to bind to the ABCC9, which obviously affects the K_ATP channel and the passage of potassium. As an example, depending on intracellular ATP, ABCC9 is able to influence the action potential duration and vasodilation in vascular smooth muscle, as well glucose metabolism in voluntary striated muscle. This could explain the roles of ABCC9 in heart disease and diabetes. As for sleep…?

KATP channels are found in the brain. In particular, in orexin neurons. This is very interesting because orexin neurons are part of our arousal system, i.e. the part that keeps us awake or not. When ATP levels begin to fall, the K_ATP channels mediate hyperpolarization of the orexin neurons, thus promoting sleep and giving our bodies time to top up on energy. If the system doesn’t work, despite having used up the surrounding ATP, we can’t fall asleep. One very intriguing illness linked to the orexin neurons is narcolepsy – a sleep disorder which causes those afflicted with it to fall asleep at any time of the day.

There is constant talk about creative insomnia and the fact that genius does not require much sleep. So does this mean that people who do are naturally disadvantaged? The phenomenon of sleep has kept all sorts of learned people busy in the past millennia. It does flirt with the mystical. One moment you’re there, the next you’re not. Nowadays, scientists can have a shot at the molecular side of things to grasp a greater understanding of the passage from consciousness to unconsciousness, and vice versa. Certainly, finding a candidate that senses metabolic status and is at the crossroads of sleep and the onset of certain diseases should be fertile ground for the development of all sorts of drugs – against sleep disorders, diabetes and heart disease to name a few.

Let there be no misunderstanding: a fly will not spontaneously drown its misery in alcohol when its female counterpart has given it the cold shoulder. But if food soused with alcohol is laid before it, the insect will show a keen preference for it. Because, like sex, alcohol is sensed as a reward. And if a reward is there to take, any animal in its right mind would go for it. Sex is a natural reward; alcohol consumption an artificial one. What the scientists set out to find was whether these two types of pleasure were governed by the same system on the molecular level. It turned out they were. In a nutshell, they discovered that drugs actually hijack the natural reward system. Which explains a lot. It is a discovery that should mark the beginning of important therapies, and which could help people who suffer from afflictions such as stress disorder or drug addiction.

For well over a century now, all sorts of scientists have been trying to understand the fundamentals of animal behaviour. Take Konrad Lorenz and his geese, or Desmond Morris and his naked ape for instance. Why does an animal behave in a certain way? And how? The field is very complex, fascinating and, in some ways, frightening. Is human behaviour, for example, solely determined by the organism’s need to survive? Does a child only enjoy an ice-cream because it spells fuel? Or has the pleasure system been diverted somehow? A bit of both no doubt. Tests can now be carried out on the molecular level and behaviourists are able to delve into the parts of animals' central nervous systems that govern given types of behaviour. Thus a neural representation of what is going on is slowly emerging.

by Thomas Mustaki

140x120cm

courtesy of the artist

Forms of stress – such as sexual rejection or post-traumatic trauma stress syndrome for instance – trigger off certain behaviours that are, more often than not, ruled by a complex reward system. When a male fly plays a love song with its wings, taps its mate gently on the abdomen with its paw, fondly buries its proboscis into the female's private parts and has to suffer rejection, the best way to get over the transient humiliation is to find something that will make it feel better. On the molecular level, Neuropeptide F (NPF) acts as a sort of 'thermometer of pleasure'. When Drosophila is denied copulation, the levels of NPF in its brain are low. When it has been able to mate, the levels are high. Low levels of NPF will make the fly seek out an alternative form of pleasure. A fly with high levels of NPF doesn't feel the need to. Therefore, NPF seems to reflect the state of Drosophila's reward system and a fly's subsequent behaviour.

How did scientists discover the link between copulation, ethanol and NPF? Male flies were isolated with three different types of females: virgins, females that had already mated, and virgins whose heads had been removed (...).The male flies were then offered food that had ethanol in it or not. The flies that had copulated ate both types of food. Those that had suffered rejection turned markedly more to the food soused with alcohol. As did those that had spent time with the headless virgins. Why behead them? This was a way of finding out whether flies suffered from rejection, as opposed to non-copulation. As it turned out, that was not the case. The 'headless virgin' males needed alcohol too. Lack of sex was the answer. Furthermore, frustrated flies that were given a chance to mate, subsequently lost interest in alcohol. So besides the direct link between two behaviours, there is also a mechanism which balances the reward system too, by bringing the levels of NPF back to normal.

The explanation sounds straightforward yet, on the molecular level, the mechanisms are far from understood. NPF and its receptor, yes, are at the heart of the system but how does it work? How does NPF link sexual behaviour with alcohol consumption? NPF is expressed in NPF neurons. The peptide has already been linked to alcohol sensitivity in Drosophila, and is known to influence behaviours such as larval intake of noxious foods and physical stress for instance. The novelty here, though, is that a given behaviour actually regulates the levels of NPF. As such, this particular regulation constitutes the basis of Drosophila's reward system. This 'reward system' NPF is probably expressed in different neurons and may be linked to the dopaminergic systems, known to play a major role in reward-driven learning.

How about humans? It is very tempting to draw parallels with the mammalian reward system. Mammals have a similar neuropeptide, known as Neuropeptide Y or NPY, which is involved in the regulation of alcohol consumption. As in Drosophila, it is likely that drugs expropriate the human reward system, twisting a natural system into something which becomes harmful to the organism though it is felt as something pleasurable. NPY levels in humans have been shown to be low in the event of depression or post-traumatic stress disorders for instance. In rats, NPY levels have been linked to alcohol consumption and drug taking. But no direct connection has yet been made between social experience, NPY and alcohol consumption. Drosophila is not a close relative, yet it undoubtedly offers an excellent model for a greater understanding of the processes underlying drug addiction, alcoholism and obesity to name a few. If NPF is injected into a frustrated Drosophila, the insect doesn't feel the need to turn to alcohol any more. Could there be something here for people who suffer from various forms of addiction? Perhaps. But let's not stop eating ice-cream.

Over time, Nature has developed a cunning way to keep seeds from germinating unless the environmental conditions are favourable. Seeds are able to remain in a dormant state for a long time – as many as thousands of years actually. The oldest seed, known to date, still had all it needed to germinate two thousand years after it fell upon the tiles of Herod the Great’s palace (73-4BC) in Israel! Besides being a very clever system, it is mind-boggling. Seeds that are able to survive so long are seeds that are in what has been a coined a “dormant” state – a little like Perrault’s Sleeping Beauty awaiting the kiss that will free her from lethargy.

A dormant seed is surrounded by a coat, itself made out of two layers – a first layer which is “dead” and rigid and a second, known as the endosperm, which is still “alive”, and in immediate contact with the embryo. Scientists discovered that when you remove the coat as a whole, germination is triggered off. This means that there must be something in the coat which represses germination. In other words, there must be something that belongs to the coat and is diffused into the embryo to keep it dormant.

Germination, by Ana Duncan

Medium: Bronze, 53 x 36 x 29cm

courtesy of the artist

The system is complex, and no doubt demands many more years of research. But the rudiments of germination are beginning to emerge. There is a phytohormone, known as ABA – or abscisic acid – which actively represses seed germination. ABA is found in the endosperm and diffuses into the embryo’s environment. How, exactly, it represses seed germination remains unclear but it has been demonstrated that its presence in sufficient quantities is necessary. The expression of this particular hormone is dependent on a protein known as DELLA protein RGL2, also found in the seed’s coat. RGL2 favours the production of ABA, thus keeping the seed in a dormant state.

The expression of RGL2 itself is dependent on the presence of another plant hormone known as gibberellin – of which there are many types. Gibberellin was first discovered in the 1920s in Japan and isolated in the 1930s from the fungal plant pathogen Gibberella fujikuroi – hence its name. This particular hormone is central in triggering off the germination process in that – upon imbibition of the seed and in the presence of other environmental cues such as favourable light conditions – gibberellin (GA) has the power to bring about the degradation of RGL2. Hence the arrest of ABA production, and the resulting capacity for the embryo to blossom. So to speak… Seed germination is therefore governed by a subtle balance between the presence of GA and ABA. With RGL2 in the midst of the two.

RGL2 is, in fact, a negative regulator of seed germination. The exact mechanism involved, however, is unknown. Perhaps it is able to repress the expression of hydrolysing enzymes, whose activity is released thanks to gibberellin. But it may also be able to prevent germination via other pathways. Only time and research will tell. One interesting fact is that it has become obvious that plant growth is not simply a case of endogenous factors responding to environmental cues, but that signalling systems such as the GA/RGL2/ABA system also interact with outside signals – giving a sense of “dialogue” to the notion of seed germination.

As always, no pathway can be narrowed down to one, two or even only three actors. Any developmental pathway is complex and involves many variables. What is certain is that DELLA protein RGL2 does seem to have more than just a passive role in the dosage of GA and ABA levels, and hence seed germination or dormancy. We are far removed from the former theory whereby it was thought that the outer “dead” layer of the coat simply formed a barrier to water and/or oxygen, or exerted a mechanical restraint on a growing embryo. Needless to say, such research is of great interest to farmers who seek to modify the time of germination for instance. Many questions remain, least of which the control of RGL2 expression. How is it abolished when germination begins? So many questions, which are not so far removed from those that surround the mystery of childbirth… What is the nature of the molecular dialogues that cause a foetus to decide it is time to move on?

In 1684, long before scientists delved into the molecular origins of our fingerprints, a British doctor known as Nehemiah Grew gave a lecture on the patterns formed by the ridges on the ends of human fingers. It was the very beginning of an awareness of the uniqueness of fingerprints. Very little interest, however, was given to the subject for the best part of two centuries until William James Herschel - an employee of the East India Company faced with high rates of local illiteracy – started to use handprints to seal contracts before turning to fingerprints as a personal signature. From then on, and due to a combination of circumstances, the use of fingerprints as a means of identification was gradually accepted and by the beginning of the 20th century, they were used not only to catalogue criminals but also to identify them.

Unsurprisingly, the power of fingerprints has spread to customs and passports. We now know that the patterns formed by the epidermal ridges on our fingertips are unique – the same pattern shared only by identical twins – and are still the surest way of identifying someone. Providing they have any… Indeed, there are very rare cases in which individuals present no fingerprints at all, because of an absence of epidermal ridges. This can be due to diseases that cause other severe handicaps, but there is also a case of adermatoglyphia which has no particular incidence on the individual other than smooth ends of fingers and problems at immigration – which is the reason the condition has also been baptised “immigration delay disease”. The first occurrence of such a disease arose from the case report of a young Swiss woman who had recurring trouble trying to get through USA checkpoints that use computerized fingerprint recognition.

Andreas Roseneder, "thumbnails & fingertips"

dedicated to the musician and composer, Franz Liszt

Chinese ink & AquaBrique on Kahari-paper, 2011

courtesy of the artist

There are life-circumstances in which people can lose their fingerprints: accidents, swelling, self-infliction and various types of labour for example. But none of this applied to the young Swiss woman. Scientists began to take an interest in her and discovered that her fingers, like her palms, toes and soles were devoid of epidermal ridges. What is more, certain members of her family presented the same problem. So the condition was hereditary. And besides a reduced amount of sweat glands, there was no other physiological complaint. So they started a search for the gene which could be at the heart of it all. They discovered an isoform that was horrendously-baptised “SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1” (or SMARCAD1…), but is otherwise known as ATP-dependent helicase 1 or hHEL1.

hHEL1 is expected to be small and globular in structure and is only expressed in the skin – which made it an ideal candidate for adermatoglyphia. It belongs to the helicase superfamily – enzymes that are able to unwind DNA or RNA, and are hence involved in gene expression and protein production. What is more, hHEL1 also seems to be able to interact not only with nucleic acids but also with other proteins. So what was the Swiss woman’s hHel1? Well, a mutation within the hHEL1 gene was found to be common to all the family members suffering from adermatoglyphia, and is believed to wipe out its function altogether. But how can it obliterate fingerprints?

As always, the malfunction of a protein gives hindsight into what its natural function could be. Human fingerprints are forged during the embryo’s life in utero, and are believed to have both a genetic and environmental origin. Pads under the growing embryo’s skin, known as volar pads, gradually disappear whilst simultaneously forming the epidermal ridges on our fingertips. By the sixth month, a foetus’s fingerprints are the ones it will have during its lifetime. It so happens that the sweat glands also form along these ridges – which would explain the sweat deficiencies on the Swiss family’s hands and feet. hHel1 must have a role in epidermal ridge architecture, and hence sweat gland formation. Perhaps via cell to cell contacts during development? So far, no one knows.

A question arises: what are fingerprints for in the first place? Surely not for promoting delays at immigration checkpoints… Until recently, it was thought that epidermal ridges were a way of increasing friction and thus giving hands, or indeed feet, a better grip. This theory seems to have lost its lustre however, and scientists now believe that the whole point of ridges may be a way of increasing sensitivity to finer sensations. From an evolutionary point of view, such an argument makes sense. Finer sensitivity spells finer tuning to an organism’s environment, which is important for its survival. In the not so distant future, DNA may well replace fingerprints for human identification. This said, mutations such as those which cause adermatoglyphia are crucial in understanding how humans are made before they appear on this side of the world.

The phenomenon of insects sliding off plant stems because of a greasy surface is known as the “greasy pole syndrome” in botanical circles. This comes from the expression widely used in politics: “climbing up the greasy pole”, which itself probably stemmed from a game which dates back to the beginning of the 19th century in which men tried climbing to the top of a 30 foot pole which had been initially smeared with grease. In fact, the insects don’t so much slip down the stems, instead they have great difficulty in creeping up them, either because they don’t get a good enough grip, or because there is a reaction between the wax and parts of their body which hinder their movements. In some carnivorous plants, for example, minute powder crystals are able to mix with adhesive fluids secreted by parts of the fly, consequently creating a kind of glue which traps the insect on the plant’s surface.

There are two types of wax in plants: glossy wax and powdery bloom, otherwise known as glaucous wax. A plant's epidermis is covered with a cuticle; wax deposited within the cuticular network creates a smooth surface on the stem, and gives the glossy wax appearance. When – and if – the cuticle is saturated with wax, organised threadlike structures, known as wax crystals, begin to form generating a thick whitish waxen layer on the stem’s surface, the glaucous wax.

Beach plum with the characteristic powdery bloom

photo by "Wildman" Steve Brill

courtesy of the photographer

What is the point of larding a stem with wax in the first place? Well, adding a layer of grease to a stem is a great way of strengthening it. It also protects it from harmful radiation, prevents it from losing water and reduces general contamination. A layer of wax is also able to check epidermal cell growth and, as discussed, it can help to keep unwanted creatures at bay. In fact, there is the surprising example of the Macaranga ant-plant whose stem is half glossy, half glaucous. While any ant – as all other insects – can saunter along the glossy part of the stem, only one ant – a Macaranga partner ant – can actually cross the glossy/glaucous threshold and continue up the stem.

Higher plants produce sterols and non-steroidal triterpenoids from a common biosynthetic pathway which starts with 2,3-oxidosqualene. Triterpenoids are the basis of cuticular and glaucous (epicuticular) wax. One particular triterpenoid, known as lupeol, constitutes almost 60% of the glaucous wax – as opposed to a mere 12% in glossy wax – thus making it an intriguing compound especially with regards to the enzyme which synthesizes it.

The enzyme in question was subsequently discovered in the powdery bloom of the castor bean and bore the main characteristics of an oxidosqualene cyclase enzyme although it has been classified as the first member of a new class of lupeol synthases. Lupeol synthase performs the last stage in lupeol formation, by cyclising the modified 2,3-oxidosqualene. When lupeol accumulates on the stem’s cuticule, it ends up building the thick threadlike wax crystal structure which, to the eye, is the characteristic whitish powdery bloom.

Researchers do not know if this particular bloom on the castor bean serves to ward off specific insects as it does in other plants. However, getting to know lupeol synthase on the molecular level will certainly be of commercial interest. Plant triterpenoids are known to have anti-inflammatory as well as anti-cancer properties. What is more, they can also be used as sweeteners, detergents and cosmetics – all fields of huge popular consumption. On a more ecological note, if scientists are able to understand, in detail, the mechanism of interaction between plant wax and how it can act as a barrier against insect predators – or on the contrary insect partners – then they can develop insecticides and pesticides which are less harmful than the more traditional repellents.

Why is an organism allergic to anything in the first place? Self-defence would be the answer. Over time, our bodies have learned to discern what it believes is good for us from what it imagines is bad. Allergies are just a way of saying it out loud. This said, is there really any point in being allergic to dairy products or wheat for example? No. Not really. Allergies are frequently a case of something potentially harmless which is seen as being harmful, so the body responds accordingly in self-defence, causing all sorts of discomfort. Nickel is not harmless. However, nickel poisoning caused by wearing an earring or answering your mobile telephone must surely be extremely rare. So what is it that causes the swelling, itches, redness and even blisters on the skin of so many people?

Much of the second half of the 19th century and the first half of the 20th were devoted to understanding the nature of an allergy on the molecular level. In the event of a skin allergy for example, there has to be something from the outside that triggers something off in the inside. In other words, there has to be some kind of molecular receptor on our skin, or under it, that can recognise an “intruder” and subsequently set off the alarm. The existence of toll-like receptors (TLRs) was mentioned for the first time in the mid-1950s. Since then, TLRs have turned out to be part of a large family of receptors – from drosophila to humans – that recognise a variety of different pathogens, mainly of microbial and viral origin.

Jeanne

by Amadeo Modigliani (1884-1920)

TLR4 is one such receptor. During the course of microbial contact, it identifies pathogen lipopolysaccharides (LPS) which – once bound to the receptor – spark off an immune reaction. Nickel is an inorganic compound which is able to do the same. And even more. Unlike other pathogenic compounds, nickel acts directly on TLR4, that is to say without the upstream assistance of adaptor proteins or even the initial presence of pathogenic LPS. So far, this is the first time that a ligand of inorganic nature is able to stimulate the innate immune system directly.

What is involved? TLR4 is a transmembrane protein which usually acts with a TLR4 twin partner thus forming a homodimer. When a nickel ion comes floating in TLR4 vicinity, it spots a part of the receptor which presents two histidines in close proximity, and binds to them. This causes the twin TLR4 to lean over and bind to the same nickel ion via the matching histidines, thus forming a true homodimer. This new TLR4 architecture constitutes the basis for an immune response and is at the very beginning of the cascade reaction following which hordes of third party macromolecules are set into motion.

The intriguing part is that scientists discovered that the histidine pocket consists in six histidines – three on each side of the homodimer. When one histidine is blocked, nickel ions are still able to bind and create an allergy. When more than one is blocked, the nickel ions do not bind and there is no immune response. This probably means that people who are spared nickel allergy lack these particular histidine residues on their TLR4s. Of greater interest for researchers: LPS is still able to elicit an immune response despite the status of the histidine pocket. This suggests that LPS is recognised by another part of TLR4 and that scientists should be able to find a site-specific treatment against nickel allergy which would not hinder an immune reaction via LPS, caused by microbial pathogens for example.

One drawback: mice are no good as a model for nickel allergy because their TLR4s do not present the histidine pocket. Which is why it took so long to understand what was going on. This also highlights the difficulty there is in considering mice as humans… However, human TLR4 has been introduced into mice, who subsequently developed nickel allergy. So researchers will be able to carry out their work. The molecular basis of immunity with regards to TLR4 is also very intriguing: here are agents which are pathogenic to certain organisms, and not to others. Take HIV for instance, to which humans and chimps are susceptible, but not New World monkeys… Could infection all be brought down to the existence – or not – of a few residues? Most probably not. However, in the case of nickel allergy, finding a way to mask the histidine residues will make life easier for millions of people. Not only for zipping up their trousers but also where cardiovascular stents or dental implants are involved. Apparently TLR4 has something to do with binge drinking too. But that’s another story…