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…

Pendred syndrome (PS) was first described in 1896 by an English general practitioner, Dr Vaughan Pendred, who had listened patiently to an Irish mother’s account of hearing deficiency which had run through her progeny composed of ten children, all of whom were almost completely deaf and mute. Some of them had also developed goitre, at an early or later age. Following the practitioner’s description, further occurrences of goitre coupled with deafness were confirmed, although, with time, it became increasingly obvious that patients afflicted with Pendred Syndrome did not necessarily also suffer from goitre. Thus making the diagnosis of PS a little tricky…

Today, far more is known both on the molecular and the physiological front, and Pendred Syndrome can be diagnosed more easily, and hence faster. The affliction is genetic and causes part of the inner ear of a developing embryo to be malformed. The result is a loss of hearing at birth. The genetic component involved in the syndrome was tracked down in the 1990s, almost exactly a century after Dr Pendred had sent the account of his findings to The Lancet at the end of the 19th century.

by Judith Scott

courtesy of the Creative Growth Art Center

The gene involved in PS encodes a transmembrane protein which has been called “pendrin”. Pendrin is about 800 amino acids long and is found in the cell membranes of three different tissues: the thyroid gland, the inner ear and the kidney – which would explain the occasional dual occurrence of goitre and deafness when something goes wrong. So far, however, there seems to be no apparent harm caused to kidneys in the event of Pendred Syndrome.

Under normal circumstances, pendrin is a transmembrane ion transporter. When malformed, it could well be that the protein is unsteady, perhaps even wobbly, within a cell’s membrane thus causing ion transport to be either faulty or even non-existent. Within the inner ear, pendrin malfunction seems to tamper with endolymph homeostasis – the fluid that flows through part of the inner ear, bathing sensory cells which are so crucial to proper hearing. This is hardly surprising since pendrin is there to ensure correct ion exchange between the outside and the inside of a cell. In turn, the disturbance of endolymph homeostasis could lead to an abnormal increase in endolymph and the consequent widening of the vestibular aqueducts – which seems to be a characteristic trait of patients suffering from PS.

Regarding the thyroid gland, little is known about how goitre occurs. Nor why. Not all patients develop goitre. Some develop it early on in life, others later, and the severity is variable. So there must be something else which triggers off the swelling of the thyroid gland, with pendrin probably playing only a minor part. As for the kidneys… Well, so far, though pendrin is also found in kidney cells, there has been no report of renal complications linked to deafness.

Until recently, patients suffering from Pendred Syndrome were most probably, and more often than not, misdiagnosed. Looking for deafness coupled with goitre was obviously not a good start – though Dr Pendred’s initial observation was astute. Currently, however, PS can be diagnosed by taking a closer look at the structure of the inner ear or, better still, by establishing a patient’s genetic profile. And the earlier the diagnosis, the better a child can be looked after. And who knows, perhaps in a few years’ time, it will be possible to restore a defective pendrin, and offer spoken words and music to those who have been deprived of them.

Deliberately suppressing the ability to remember something may sound unreasonable. Yet the art of forgetting is also important. We have to forget all the words we hear throughout the day. We have to forget all the prices we see on a restaurant’s menu. We have to forget all the faces we brush past as we rush across town. Our brain needs to filter the hundreds of thousands of messages we bump into every day. If it doesn’t, we would all be on the verge of madness. Memory is thus a question of balance between remembering some things and forgetting many others.

The notion is not new. There is a psychiatric disorder known as the Savant Syndrome* caused by the malfunction of a phosphatase, PP1, which – in natural circumstances – hinders the synthesis of proteins involved in memory. Those inflicted with the disorder are submerged with useless information they are unable to forget. Hence, the importance of a basic memory filter. So why all the fuss about RGS14? Because RGS14 not only belongs to a part of the brain which, until now, had shown no involvement whatsoever in the memory process but also because when it is shut off, memory seems to be enhanced without any side effects. Which sounds like magic...

by PET

courtesy of the artist

Current wisdom suggests that, in the brain, the seat of memory and learning is situated in the hippocampus. Until recently, one small region known as CA2 had been neglected by researchers because – unlike the rest of the hippocampus – it didn’t seem to have any say in memory. But it turns out that it does, in a certain sense. Indeed, CA2 is full of RGS14. So, yes, in natural circumstances, RGS14 suppresses the faculty of memorising. But when the protein was silenced in mice, scientists discovered that the rodents were not only intrigued by new objects – thus meaning that they had recognised pre-existing ones which were consequently of less interest – but they were also far brighter than their wild-type companions at making their way through a maze.

So what is happening on the molecular level? The answer is synaptic plasticity. Memory is believed to be a case of synaptic transmission between neurons, and the strengthening of such connections. This has been termed synaptic plasticity and forms the basis of acquiring and consolidating certain forms of learning and memory. These processes are known to occur in the hippocampus, save in the CA2 region. Which is one of the reasons this region had been ignored until now. So, if synaptic plasticity is at the heart of memory, how does RGS14 act upon it?

RGS14 belongs to the very large family of G protein signalling regulators (RGS) and directly suppresses the activity of a certain number of proteins whose downstream effects would otherwise be crucial in the processes of learning and memory. More specifically, RGS14 binds to G proteins as well as to components of the mitogen-activated protein (MAP) kinase signalling pathway – both of which are required to strengthen synaptic transmission. When the effects of RGS14 are wiped out in mice for example, G protein and MAP kinase signalling pathways are free to be activated, synaptic plasticity is restored and the rodents’ capacity to remember objects is enhanced. Thus making them somewhat smarter than they otherwise were expected to be.

What is more, putting a rein on RGS14 doesn’t seem to have any side effects on the mice’s psyche. For as much as one can really measure such a subtle state of things. But, once again, a mouse is not human, and there is a great chance that RGS14 is part of our brain – or a rodent’s – for a reason other than memory. To be sure, the rest of the hippocampus does that… Perhaps RGS14’s faculty of suppressing memory is just a side effect of something far more important it can do that we are unaware of. After all, the loss of neurons in the CA2 region is known to be involved in psychiatric disorders such as schizophrenia for instance. This said, RGS14 is restricted to CA2, itself a discrete region of the hippocampus, which makes the protein an ideal candidate for the future design of therapeutic agents that could ease psychiatric disorders. Or simply help to diminish the increasing ease with which we forget things over the years.

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*N.B. Also read Protein Spotlight issue 32, “The things we forget”

Parkinson’s disease was named after the scientist cum politician James Parkinson (1755-1824) who was the first to describe what he called Paralysis agitans, or the Shaking Palsy. Apparently he never examined anyone in depth, but made keen observations on six individuals whilst on his daily strolls, sometimes inquiring into the history of their symptoms. Indeed, it is less for his activities as a surgeon, geologist, palaeontologist or political activist that Parkinson is known but more for the publication of his now classical “Essay on the Shaking Palsy”, written in 1817. And, as a tribute to his pioneering observations, the French neurologist Jean-Martin Charcot (1825-1893) renamed the illness “Parkinson’s Disease” 60 years later.

There are two prevalent neurodegenerative disorders, one of which is PD – an infliction most of us are acquainted with. We have all encountered people whose hands tremble unceasingly – a common symptom of PD. Others, which are perhaps less obvious, involve rigidity, slowness of movement and balance problems. This is due to the death of specific neurons involved in dopamine transmission. Dopamine is part of many brain activities, including voluntary movement, sleep, mood, attention and motivation. People are usually inflicted with PD after the age of 50 but, in some cases, the first symptoms can occur at a far earlier age. Currently, scientists believe that some early forms of PD are the fruit of mutations in the protein Parkin – mutations which can be inherited.

© Road Tears (2011), by Robyn Michele Levy*

As always, it was the discovery of mutations in Parkin that led to the understanding of its role within neurons in the first place. In particular, Parkin seems to be involved in the process which gets rid of damaged proteins within dopamine-containing neurons. Damaged proteins, hence undesirable proteins, must be cleared to sustain a proper turnover of any given protein. How does Parkin do this? In a nutshell, Parkin is able to add small molecules – known as ubiquitin – in a totem-like way, onto a protein that is defective. The resulting ubiquitin tag on the protein’s surface acts as a signal for a proteasome, which will spy the tagged protein and subsequently degrade it.

The molecular structure of Parkin is quite well known. Its N-terminus is ubiquitin-like, while its C-terminus is reminiscent of the E3 ubiquitin-ligase family, i.e. a domain which involves one IBR (for In Between Region…) domain sandwiched between two RING (for Really Interesting New Gene…) fingers. The second RING finger binds the E2 ubiquitin-conjugating enzyme. In turn, Parkin is able to act as an E3 ubiquitin-ligase and recognises its target protein via its N-terminal, to which it will add ubiquitin.

In particular, one of Parkin’s target proteins in dopamine-containing neurons seems to be CD-Crel-1, a synaptic protein. A protein of relevance since it is involved in the proper function of the synaptic vessels which transmit dopamine from one neuron to another. If, for any given reason, Parkin is defective, it will cause an imbalance in CD-Crel-1 turnover, which is bound to have an effect on dopamine transmission, hence in brain activities such as involuntary movement for example.

It certainly seems to be the perfect explanation. However, this is just one theory. PD is a complex disease. Scientists are well aware that there are many mutations in Parkin which are capable of causing PD. What is more, these mutations may well have different effects on different proteins – each of which have a different role. And Parkin is not the only gene known to be involved in Parkinson’s… As always, only part of the way has been paved. Yet it is an important one. The knowledge of the intimate structure of Parkin could ultimately lead to the development of therapies which would adjust protein turnover and keep dopamine-containing neurons alive.

________________________________________

* Robyn Michele Levy is a visual artist, radio broadcaster, and writer. At age 43, she was diagnosed with Parkinson’s disease and, eight months later, with breast cancer, and has just written her memoir: “Most of Me: Surviving My Medical Meltdown”. She lives with her family and her remaining body parts in Vancouver, British Columbia.

A bee’s world is very much a lady’s one. Female bees nurse, make wax, produce honey, attend to the queen, build the honeycomb, pack the pollen, fan the hive, guard the premises, carry water and forage for nectar. While the male bees – known as “drones” from the old English “draen” meaning “male honeybee” – are somewhat idle and do nothing but wait for an opportunity to fertilise a virgin queen. Following which, they die. A drone’s life is therefore short and sweet, barely a few months long. A queen’s life, however, can last for as long as two years.

The worker bees – all female – have been given the astonishing ability to decide whether a larva is to become a queen or not, and when. A faculty which has baffled biologists: which of the two – the queen or her subjects – really has the power? It is a sort of chicken or egg dilemma. Certainly, a hive needs worker bees to produce the royal jelly – something they secrete from their cephalic glandular system – which they will then inject into the cell, fully immersing the queen-to-be larva in the viscous product. From this point onwards, the larva will develop much faster than any of the other bees. It will also become bigger, its ovaries will develop and it will live far longer than any of its siblings. More importantly, once fertilised by a horde of indolent drones, it will lay a mere 2000 eggs a day!

larvae immersed in royal jelly

wikimedia

Royal jelly is a mixture of moisture, protein, sugar, lipids, vitamins, salts and free amino acids. The greater part of its protein content is made up of one protein family known as MRJP, for major royal jelly proteins. There are five members in this family, one of which is MRJP1, otherwise known as royalactin. Royalactin is a modest-sized protein that acts on its own. It somehow manages to avoid degradation within the larva’s digestive system and, instead, acts much in the same way as a hormone would, by triggering off a whole series of metabolic processes that are characteristic of a queen’s development.

How royalactin actually achieves this still remains obscure. It may well reach the larva’s fat body, which is a sort of dispersed tissue in the insect’s abdomen that is thought to store energy and be able to control development and metabolic processes. In the fat body, royalactin seems to have the potential of setting off a number of developmental reactions via the epidermal growth factor (EGF) mediated signalling pathway, either by acting as an EGF ligand or by giving a wake-up call to other EGF ligands. Following this, three major events take place: 1) the larva’s body size increases via P70 S6 kinase, 2) development time is shortened by way of mitogen-activated protein kinase, and 3) the ovaries mature thanks to juvenile hormone. And last but far from least, royalactin also seems to have the capacity to lengthen the queen’s life-span.

So royalactin is directly involved in making a queen out of a bee, but it can still do more. Or at least parts of it can. Its protein sequence is sometimes cleaved to give rise to three small antimicrobial peptides, known as jelleines. This is hardly surprising, since royal jelly is prone to bacteria or yeast colonisation, what with worker bees bringing in products that are external to the beehive, such as honey and pollen. Jelleines probably assemble to form pores in the bacterial and yeast membranes thus making them permeable and hence fragile.

Biotechnological companies are always on the lookout for novel antibiotic drugs, and the smallness of insect antimicrobial peptides is ideal for such technology. Research in this field is only just beginning, as is that carried out on royalactin and queen differentiation. It is a fascinating field of study for biologists. What is more, royal jelly has always been regarded as a kind of panacea and believed to have vasodilative, hypotensive, antitumour, anti-hypoercholesterolemic, disinfectant and anti-inflammatory activity – to name a few. And if it can turn a bee into a fertile and long-living queen, would you not be inclined to take it by the spoonful?

The term “schizophrenia” was coined by the Swiss psychiatrist Eugene Bleuler, in 1911. Until the very end of the 19th century, psychiatric disorders had certainly been diagnosed but it was only in 1887 that the German psychiatrist Emil Kraeplin tried to classify them. In so doing, he suggested “dementia praecox” – or premature dementia – to sum up the symptoms of what is now defined as schizophrenia. Eugene Bleuler changed the name because Kraplin’s designation suggested a gradual mental deterioration, which is not necessarily the case.

Centuries ago, the causes of mental disorders were believed to be the doings of evil spirits that had taken possession of a body. The treatment proved to be as naïve as the times were in medical knowledge, and patients could be subjected to extreme treatments, such as the drilling of holes into their skulls through which the demons were released. Alternative and less drastic treatments also existed, one of which was the exposure of patients to certain types of music – a therapy that is not far-removed from a current alternative therapy known as the Tomatis Method, in which music is used to help alleviate mental disorders such as autism or depression for instance. Until relatively recently, people suffering from psychosis spent a great part – if not all – of their adult life in asylums. Thankfully, during the second half 20th century, great advances were made in the field of psychiatry and many patients suffering from mental disorders are now able to live an independent – albeit marginal – life.

by Frédéric Aeby

Courtesy of the artist

Such advances include the medical treatment of schizophrenia, which affects as much as 1% of the general population... Running thoughts, delusions, hallucinations, social withdrawal, lack of affect and deficits in executive function are only a few of the disturbances characteristic of someone suffering from this particular form of psychosis – a number of which may even appear before the onset of the illness. This is why the recent discovery of neuregulin-1 and its probable involvement in schizophrenia is encouraging. But what, exactly, has been discovered?

Neuregulin-1 is a signalling protein that mediates cell-cell interactions and plays a critical role in organ development. There are four isoforms. Isoform type IV is particular to the nervous system, and is greatly expressed in the foetal brain – and to a lesser degree in the adult brain – where it is thought to be at the heart of neurogenesis, neuronal migration, synaptic plasticity and the regulation of neurotransmitter function. It is hardly surprising, then, that the deregulation of neuregulin-1 can bring about psychiatric disorders. A mutation within the promoter region of the neuregulin-1 type IV gene is believed to be the culprit. This mutation causes the protein to be expressed differently and lays the foundations, very early on in life, of a psychiatric fragility whose symptoms usually first appear during the later years of adolescence – given the unfortunate circumstances.

Neuregulin-1 is expressed in neurons and secreted at the synaptic cleft, where it binds to a receptor known as ErbB4 situated on the postsynaptic membrane. This action sparks off a signal which is relayed further, ultimately fuelling a variety of pathways all involved in brain development. One hypothesis could explain the onset of schizophrenia: the effects of neuregulin-1 on synaptic plasticity via glutamatergic transmission. Abnormalities in plasticity may explain cognitive drawbacks characteristic of schizophrenia, such as deficits in memory, attention and executive function.

One surprising discovery is that the neuregulin-1 isoform which predisposes to schizophrenia also seems to protect carriers from cancer. Why? No-one knows. As no one can say in what way neuregulin-1 is able to galvanise creativity. Naturally, there is no way that one sole protein could have such intimidating power. Brain development is hugely complex and involves myriads of intricate biological pathways. However, this particular brain-specific neuregulin-1 may well prove to be precious for the design of drugs which would not have the violent side effects current medication has on patients. And is it not intriguing – not to mention somewhat daunting – to realise that psychiatric fragility and creativity are, perhaps, not only related but may also be inheritable?

The notion that plants are able to self-pollinate is not new. Charles Darwin, who is widely known for his thoughts on the evolution of primates, also spent a lot of time making observations on countless other organisms, including plants. He had already suggested the existence of self-fertilisation during the second half of the 19th century – and even dedicated a book to the notion, The Effects of Cross and Self Fertilisation in the Vegetable Kingdom (1876).

Why would plants seek to self-pollinate? The answer seems obvious. When you can’t find someone else to do it, do it yourself. It is not in the pursuit of pleasure that a plant would end up self-pollinating but rather in the hope of guaranteeing successful growth within a given environment; an environment that has become hostile enough to make cross-breeding difficult, yet in which the disadvantages of in-breeding are outweighed by the advantages…

Hermafrodite, by Lisbeth Hummel

Courtesy of the artist

In the past few years, scientists have been studying one particular system in Arabidopsis thaliana, which has proved to be an essential part of an elegant process that has been coined “self-incompatibility” (SI). SI is used by plants to avoid self-pollination, thus ensuring genetic variation and population vigour. In a nutshell, plants whose SI system is working properly are not able to self-pollinate. It sounds straightforward enough, yet the SI system is turning out to be a complex one. However, what has been termed the S locus seems to play a pivotal role and is best illustrated by its protein products: s-locus receptor kinase (SRK) and s-locus cysteine-rich protein (SCR).

SRK is a transmembrane receptor protein, which probably forms a homodimer and is found on the very tip of a flower’s pistil, known as its stigma. The stigma forms a kind of platform on which pollen is able to land, hydrate, germinate, and ultimately push its pollen tube all the way down the pistil to the ovary to complete fertilisation. SCR is found in the pollen’s outer coat and is secreted when pollen approaches the stigma. If the pollen and the pistil belong to the same plant, SCR and SRK belong to the same S locus and, like glove in hand, SCR will bind to SRK. Their binding then triggers off an alert system – probably via SRK phosphorylation – which interrupts pollen tube growth. As such, the system functions much like passing through customs – if the pollen belongs to the same plant, an alarm goes off and fertilisation is immediately stopped. It has been suggested that this happens by the degradation of actin filaments which support pollen tube growth.

This is how SI works for many plants. In A.thaliana, however, due to numerous mutations over time, the S locus has been out of order for about half a million years. As a consequence, when A.thaliana’s pollen settles on the tip of its own pistils, SCR is not recognised by the plant’s SRK. Consequently, the SI alert is not set off and the pollen is left to germinate and make its way down the pistil to the ovary.

As always, no given pathway can be trimmed down to the likes of one or two proteins. Indeed, though a key element in plant self-incompatibility, the S locus is not the only decision-making entity in the SI pathway. A cascade of decision events occurs downstream and many other processes – such as pollen/stigma recognition, pollen hydration, germination and directional growth – upstream. Nevertheless, A.thaliana is turning out to be an excellent plant model for studying signalling pathways.

From a purely biological point of view, in-breeding – not to mention incest – has never been encouraged within a species, mainly for its healthy survival. Here’s a thought: is it not amazing that the plant kingdom has resorted to a genetic system to discourage in-breeding, while humans count on words and cultural heritage?

Why 5-HT? 5-HT is an abbreviation for 5-hydroxytryptamine which is the chemical structure of serotonin. Although serotonin is still the term which is widely used, it has become inaccurate. And it wasn’t even its first designation… Indeed, in the 1930s, Dr. Vittorio Erspamer discovered a substance that was able to contract intestinal muscles. His contemporaries believed that it was adrenaline but Erspamer demonstrated that it was in fact a then unknown amine, which he called enteramine. Almost twenty years later, Drs. Maurice Rapport, Arda Green and Irvin Page came across something in the blood serum that could affect vascular tone, and they called it serotonin. In 1952, however, it became obvious that enteramine and serotonin were one and the same thing. Over the years, though, serotonin has proved to be so versatile that scientists prefer to strip its name down to its essentials, hence 5-HT.

Serotonin’s versatility is really just a consequence of the many different receptors it is able to bind to. To date, there are seventeen different types of 5-HT receptors able to trigger off a wide range of activities. Structurally, they are all pretty similar but they have been neatly arranged into seven different families based on their structural or physiological differences. Despite these differences, they are transmembrane G-protein coupled proteins – save one family whose members are cation channels – most of which are intimately involved in blocking or transmitting signals in the central nervous system.

Zägg, by Isabelle Kurmann

Courtesy of the artist

isabellekurmann@hotmail.com

Indeed, most serotonin receptors are made in the brain – though their action is not limited to this part of the body – and are found in the region of the receiving end of the synaptic junction, where they span the membrane. Their role is to await the release of serotonin, bind it, thus relaying whatever signal is to be relayed. Depending on the type of receptor, the message is very different. As mentioned above, the regulation of mood is one such message and 5-HT receptors are one of the major molecules involved in the effects of the famous – or infamous perhaps – hallucinogenic substances such as LSD. They are also involved in drug addiction and, as recently demonstrated, can participate in behavioural disorders such as impulsivity.

Impulsivity is defined as behaviour which lacks both inhibition of an act and the consideration of consequences following it. The 5-HT2B receptor seems to be the receptor which is able to relay such behaviour. Or indeed a certain variant of 5-HT2B receptor which – so far – has only been found in Finns. In an intriguing piece of research, scientists tested a population of Finnish prisoners who had been convicted for criminal offence in which impulsive behaviour had been diagnosed. They were able to demonstrate that many of the prisoners carried the same variant of the 5-HT2B receptor – a variant which resulted in a non-functional 5-HT2B receptor. Naturally, this does not mean that only Finns suffer from impulsivity. Or indeed that criminality is hereditary. But what it does demonstrate is that, within a given population, impulsivity certainly seems to have a genetic basis.

Does this mean that impulsivity is passed down generations? Impulsivity involves behaviour which can lead to suicide, addiction and violent criminality for instance, but this does not mean that everyone carrying the 5-HT2B receptor variant will necessarily commit suicide, succumb to drugs or kill another human. Like so many other disorders – schizophrenia to name one – our environment is paramount in triggering off certain behaviours. In the case of this particular 5-HT2B variant, factors such as being male, testosterone levels and alcohol played an important part, but there are no doubt many others, not to mention stress.

The 5-HT2B receptor also happens to bind 3,4-methylenedioxymethamphetamine – or ecstasy – a molecule generations of young adults have been popping into their system on Saturday nights for the past few decades. Needless to say, 5-HT receptors are certainly at the heart of modified behaviours of all sorts and it comes as no surprise that they are therapeutic sites of choice for the design of antidepressants, anxiolytics and anti-obsessional drugs for example. The human psyche and its making will always be part of life’s mysteries and it is always very reassuring to realise that though genetic factors make up the basis, besides serious psychiatric afflictions, our behaviour, like our personality, are also modelled by what surrounds us, including – one would hope – our own free will.

Tubes, tunnels, pores, subways, holes, shafts, you name it, are all very straightforward ways of getting something from one place to another. Engineers build them to go through mountains and under seas. Electricians use them as motorways for electrons. On a far smaller scale, nanoengineers design them so that matter can flow from one place to another. But that is all very recent. Nature devised hollow architecture billions of years before anyone else. From bacteria to tulips and humans, all sorts of pores are used to relay all kinds of messages either within a cell, or from one cell to another. These minute biological passageways are used as a means to relay messages, and are involved in events as diverse as defence, sex, smell, transpiration, sleep and the beating of a heart.

When a cell has become unwelcome – because it has been infected or has become malignant – the immune system triggers off an initial response, known as the innate response. This immune reaction is immediate. Natural killer cells armed with poison are deployed and are able to recognise the hostile cells. Upon recognition, various enzymes make their way into the infected cells’ cytosol by way of perforin pores and, together, they trigger off cell apoptosis. How exactly the killer enzymes reach the cytosol remains obscure. To date there are two theories.

Big Bang, by Emanuela Lucaci

Courtesy of the artist ©2004

The first suggests a simple strategy. A natural killer cell approaches a target cell and releases perforin and other enzymes into a cleft between them. Here perforin monomers assemble to form a multimeric barrel-shaped pore which is then inserted into the hostile cell’s plasma membrane. The apoptotic enzymes are then able to flow into the infected cell and get on with their business. The second theory is very similar; the difference is geographical. Indeed, perforins together with the killer enzymes are believed to enter the infected cell by way of endocytosis. Pore formation then occurs within an endocytic lysosome. Once assembled, the pores are inserted into the lysosome’s membrane, and the apoptotic enzmyes are released into the infected cell’s cytosol.

Whichever the strategy, the end result is the assembly of perforin monomers to form transmembrane pores through which flow apoptotic enzymes. A perforin monomer has a key-like structure. The main body of the structure is an intricate mass of alpha helices which embrace a series of beta sheets. The “tail” of the key-like structure is formed by yet another series of beta sheets. And the two regions are joined by a domain which is highly flexible, and vulnerable. When pore formation is launched, about twenty perforin monomers assemble neatly to form a barrel-shaped pore large enough for the passage of apoptotic enzymes. It seems that the pores are formed before they are actually inserted into the plasma membrane. In order to do this, the alpha helices stretch and flatten out alongside the existing beta strands, and the now smooth barrel-shaped structure is ready to glide and lodge itself into the lipid bilayer.

Perforins, however, are more than just pore-forming entities. Indeed, without them, the apoptotic enzymes – in particular enzymes known as granzymes – are unable to carry out their toxic effect. This would imply that the presence of perforins in the immune response is more than merely architectural. To date though, nothing more is known about alternative perforin activity. There remains an intriguing question however. How can perforin and its accompanying killer enzymes destroy unwelcome cells and yet not affect the cells that release them? As logic would suggest, the system could easily act against the killer cells themselves. It has been implied that soluble perforins are covered in a bulky protective coat of proteoglycans, which would prevent them from turning onto the cells which carry them.

Needless to say, perforin is so essential to the immune response that a faulty version of it, or its absence, can only spell disaster. And indeed, there is a hereditary disorder known as HLH (hemophagocytic lymphohistiocytosis) in which patients suffer from a total loss of lymphocyte cytotoxic function because of a loss of perforin activity. What is more, it has been observed that severely immunosuppressed transplant patients are prone to developing cancers – which may well be due to the drastic down regulation of cytotoxic cells caused by a counter performance of their perforins. This is why it is so important to get to know perforin better so that, in the near future, drugs will be designed which could either restore incorrect perforin folding or perhaps replace perforin altogether to recover a healthy immune response.

* Another kind of tunnel. This painting by the Swiss artist Emanuela Lucaci covers the outer doors of the ALICE magnet which is part of the LHC tunnel at the European Organisation for Nuclear Research (CERN).

The term “dyslexia” was coined at the end of the19th century, literally describing a person’s disability to read text out aloud. James Hinshelwood, a British ophthalmologist who wrote a book about the disability in the early 1900s, actually referred to it as a congenital word blindness. Whereas, in the past, “stupidity” was the usual word used to qualify schoolchildren who could not cope with texts, today dyslexic pupils are no longer considered retarded but are – more often than not – granted special attention. Especially since, in our society, such a handicap can turn out to be a big disadvantage on the economic and social front.

The finding that dyslexia could be hereditary prompted scientists to find out which gene – or genes – could be involved. To date, scientists know of about a dozen which may all have some kind of role in dyslexia, although which is unknown. However, one gene in particular – KIAA0319 – is promising in that it seems to be involved in neuron adhesion and migration, i.e. in brain development. What is more, one of its isoforms has been found specifically in people suffering from dyslexia.

Jazz, by Tak Salmastyan

Courtesy of the artist

What exactly does KIAA0319 do? From a structural point of view, it hardly deserves to be mentioned. KIAA0319 is a pretty straight-forward transmembrane protein, found in the plasma membrane of neurons. It sports quite a large C-terminal end that sticks out in the extracellular space and a small N-terminal end that protrudes into the neuron’s cytoplasm. The C-terminal end is highly glycosylated and carries five domains known as PKD (polycystic kidney disease) domains and one MANEC (motif at the N terminus with eight cysteines) domain.

Interestingly, PKD domains are known to be involved in cell to cell interactions or cell adhesion. In KIAA0319, the extracellular PKD domains may mediate adhesion between neurons and glial cells – the cells which support and protect the brain’s neurons. As such, KIAA0319 may play a part in neural outgrowth as well as neuron migration during brain development – thus linking dyslexia to a problem in neural development at an early age.

The most intriguing part of KIAA0319, however, is the way it behaves once it has seemingly served its purpose, i.e. ectodomain shedding and intramembrane cleavage, also known as RIP (…) short for regulated intramembrane proteolysis. Indeed, KIAA0319 literally falls apart, casting its proteic splinters either outside the neuron or within it. It is thought that at least five different cleavage events occur, four of which segment the C-terminal end into small peptides which are disseminated in the extracellular matrix. No one knows what their destiny is – if any at all – but they could trigger off other activities elsewhere in the brain. As for the intramembrane domain, it is released into the neuron’s cytoplasm by way of endocytosis where it translocates to the nucleus. Could it be involved in gene regulation at this stage? Perhaps. What is sure, however, is that the collapse of KIAA0319 is one very effective way of regulating neuron migration.

People suffering from dyslexia carry a KIAA0319 isoform which causes the protein to be less expressed. As a consequence, less of it is available for neuron outgrowth and migration thus causing a mild malformation of part of the growing brain. As such, dyslexia is an intriguing handicap for biologists and neuroscientists alike. How is it that a part of the brain which is “malformed” can affect specific cognitive functions such as a reading disability while preserving intelligence on the whole? Another very interesting development is the notion that, as is the case for psychiatric illnesses, there could be a genetic predisposition to dyslexia. Indeed, people carrying the KIAA0319 isoform may not necessarily suffer from dyslexia. However, given a certain environment, the handicap may be triggered off.

In reality, though much progress has been made, dyslexia remains very much of a conundrum. It has been noted that many of the genes and their protein products are also involved in neuronal plasticity. Perhaps it is more this feature than neuron migration which has something to do with the affliction. What is more, it is not one sole gene, or protein, which is guilty of meddling with the brain but a network of molecules which interact. This said, such studies are great for shedding light on brain development as a whole, and understanding the effects of environment on disorders which can arise later on in age. In the long run, it may also shed some light onto why humans can read, and why their fellow apes cannot.

The term “migraine” is from the old French “migraigne” derived from “hemicrania” – literally meaning “half a skull” – a term used by the Greeks to describe these debilitating headaches which typically affect one side of the brain. Over the centuries, suggested remedies could be as drastic as applying a hot iron to the head or inserting garlic into an incision made in the temple. Some migraines – one third in all – give off tell-tale signals known as the aura, which warn those suffering from them of an oncoming attack. These signals are caused by neurological disturbances which are frequently visual – such as black spots, hallucinations or scintillating shapes – but can also be sensory such as limb weakness or a pins and needles sensation for instance.

Women suffer from migraine attacks more than men do. Why remains a mystery. Could it have something to do with their menstrual cycle? Possibly. Menopause certainly does seem to be one of the best ways to diminish migraine episodes. This said, there is no question that both genders are prone to the attacks. So what is it inside us which throbs? In the past years, researchers have managed to link a handful of genes to migraines but no one could point to one gene in particular. Until a few scientists discovered that a specific mutation in TRESK – for TWIK-related spinal cord potassium channel – could cause hereditary migraine with aura.

Migraine Aura, by Pet Serrano

Courtesy of the artist

TRESK is one of the many types of potassium channel which has four transmembrane domains and two pore domains – themselves sandwiched between the first and second, and the third and fourth transmembrane domains. The importance of potassium channels was first recognised in the 1950s when researchers were developing the concept of electrophysiology and membrane potential, and realised that potassium channels were at the heart of cell to cell communication. Indeed, as could be expected, potassium channels are found in every cell type of all forms of life and are known to be involved in a variety of physiological functions such as heart rate, muscle contraction and hormone secretion to name a few.

TRESK is found in the human spinal cord and brain. So, besides letting potassium ions through neuron membranes, what is the purpose of this particular channel in our central nervous system? It seems that TRESK has a direct role in the regulation of neuronal resting membrane potential as well as neuronal excitability – obviously of utmost importance when it comes to brain function. It has been suggested that the channel has a specific role in the pathway to pain and, conversely, in general anaesthesia. In the event of migraine with aura, a particular mutation in TRESK causes the channel to lose its function completely by truncating the second transmembrane domain in the channel. As a consequence, TRESK is unable to regulate neuronal excitability and – upon certain environmental cues such as bright lights, alcohol or tiredness – the first signs of neurogenic disturbance occur, soon followed by the characteristic debilitating painful pulses.

Since this particular mutated form of TRESK – and no doubt other mutations on the same protein, which remain to be discovered – has a direct role in causing migraines, an obvious therapeutic strategy would be to find a way to upregulate TRESK activity. Furthermore, the effects of TRESK inactivity could explain why patients who have to rely on immune-suppressants frequently suffer from migraine episodes. Indeed, immunosuppressive therapy involves calcineurin inhibitors which, in turn, inhibit TRESK function. There may be hope then for migraine sufferers who could benefit from such therapies either by using them as an immediate painkiller or as a prophylactic.

This could be great news for something which paralyses about 10% of the world's population. It has been estimated that migraine headaches are the most costly neurological disorder in the European Community – what with the medical costs involved and the consequent loss of professional productivity. However, finance and the work place aside, just a means to alleviate the throbbing pain which accompanies migraines is enough to look forward to and would offer a far more comfortable life to those who suffer from a chronic form of the condition.

There are few feelings more beneficial to a human than those triggered off by love. But love was not given to us for therapeutic purposes. From a purely biological point of view, where poetry has little room, we fall in love for a reason. Indeed, falling in love means falling for a mate. Falling for a mate means – to put it bluntly – sexual intercourse. And sexual intercourse means perpetuation of the species. What is more, falling in love – or so it is believed – is a way of ensuring fidelity, which is far less time- and energy-consuming in the realms of sex than infidelity. Hence, according to such a theory, love would be the doings of evolution. You can agree with it. Or disagree with it. But it has its logic.

Once you start meddling with the notion of love and its chemistry, the curious mind wants to know which chemical entity could be actively involved in such a feeling. In this light, scientists compared a human’s psychological state during the early stages of romantic love with obsessive-compulsive disorder (OCD). The neurotransmitter serotonin, or to be more precise the protein which carries it and is known as serotonin transporter, has a role in OCD in that its concentration is lower in patients suffering from the psychiatric condition than it is in healthy individuals. When individuals madly in love with someone were tested for the level of their serotonin transporters, the scientists found that – like OCD – their concentration was lower. Could that be where the term “lovesick” comes from?

Absence makes the heart..., by Ben Lawson

Courtesy of the artist

Besides OCD and romantic love, serotonin and its transporter are known for their involvement in mood and behaviour. Neurons filled with serotonin are found in all parts of the brain – which goes to show their importance. The serotonin system seems to be critical in child brain development and the branching out of serotonergic projections. Later on in life, this particular branching or indeed the specific serotonin transporter polymorph that an individual has inherited, can give rise to differences in behaviour and moods depending on the environment. In particular, one individual can be more prone than another to developing a certain type of psychiatric disorder following stressful situations, depending on the type of serotonin transporter he or she carries. Scientists even suggest here a basis for a difference in masculine or feminine moods or even psychiatric predisposition.

So the serotonin transporter, small as it is, has a far-reaching role in our lives. But how exactly does it work? Serotonin transporter is an integral membrane protein found in the cell membrane of neurons at the level of the presynaptic terminal, one end of which protrudes into the synaptic cleft. This is the part which grabs free serotonin and flings it back into the neuron ready for a new neurotransmitter cycle. But it needs ions to help it. First Na+ binds to the empty transporter in the synaptic cleft. This is the cue for serotonin to bind, followed closely by Cl¯. The threesome then causes a conformational change in serotonin transporter which flips around bringing the part which is usually immersed in the synaptic cleft into the neuron cytoplasm. There it releases the serotonin molecule, thus replenishing the neuron with its neurotransmitter which is now available to spark off a variety of moods. The binding of intracellular K+ then causes the transporter to flip back into its original position with the receiving end in the synaptic cleft; K+ is released and serotonin transporter is ready to bind another ligand.

Consequently, it is not difficult to understand that serotonin transporter is crucial in regulating serotonin activity as well as homeostasis, and thus has a pivotal role in the regulation of moods and behaviours – with normality at one end and mental disorders at the other, notably when the level of serotonin transporters is low. Besides romantic love, the serotonin transporter system is believed to be involved in many other types of behaviours such as appetite, sleep, sex, arousal, addiction, impul-siveness, anxiety, depression, OCD, alcoholism, autism…and even spiritual experiences.

The “romantic love versus OCD” hypothesis has met with scepticism. The individuals chosen for the study were certainly in love but none of them had had sexual intercourse with the ones they had fallen for. This was a prerequisite as the scientists defined romantic love as love where sex had not yet proved to be part of the bargain. This met with controversy. Were all these individuals not just suffering from stress caused by an unsatisfied desire due to repetitive procrastination? A behaviour not so far removed from OCD…

Unsurprisingly, the serotonin system is already a principal site of action of therapeutic antidepressants. Further knowledge of it will provide a greater understanding of the role of serotonin in brain development, the neurocircuits involved in emotional processing and, perhaps more importantly, the basis of a number of neuropsychiatric disorders which could then be the basis for the design of novel psychiatric drugs. So can romantic love really all be brought down to chemistry? And to this chemistry in particular? It will probably always remain a mystery. Is it not daunting, though, to take on board the fact that molecules can have such power over our emotions? And yet, without chemistry, we know that feelings would not exist. Talk about chemistry between people…

Why do we breathe in the first place? The question really is: why do we need oxygen? Oxygen is used in the process which makes energy out of the food we eat. Without it, we would not be able to synthesize ATP and our body would therefore be deprived of the vital molecule which drives all the biosynthetic pathways and physiological processes we need to keep us alive. In order to capture the oxygen, Mother Nature provided us with airways – such as lungs and a nose – to breathe it in, and blood to distribute it to every nook and cranny of our body. Likewise, the same airways and blood system get rid of carbonic dioxide which is the waste product that arises from the use of oxygen. Consequently, the process of breathing in, and breathing out, is paramount to say the least, and perhaps best illustrated by the notion that life is determined by both our first breath and our last.

The act of breathing is a complex one. It is not just a matter of letting the surrounding oxygen leak into our nose or mouth, from where it will drift into the blood system. Two airways – the upper one and the lower one – have to be set into motion. In a nutshell, the upper airways are the system we use above our shoulders to provide an air flow, such as our nose and the windpipe; the lower airways are situated below the neck, such as our lungs. When a newborn finally emerges from its mother’s womb, a whole set of muscles, airway openings, motoneurons and hordes of biochemical pathways are triggered off so that the first breath of air can enter the mouth and be pushed down to the lungs which will have just started their rhythmic movement for a lifetime of inhalation and exhalation.

Life's First Breath, by Maria Pace-Wynters

Courtesy of the artist

Teashirt 3 is not a newly discovered protein. It belongs to the large family of zinc finger proteins which are transcriptional regulators, so named because they use zinc ions to stabilise internal structural folds that are capable of binding typically to DNA or RNA. Teashirt 3, in particular, is involved in the regulation of developmental processes within the upper and the lower respiratory system, as well as in the differentiation of uretic smooth muscle for instance. It is also known to be involved in the development of Alzheimer’s disease together with caspase 4. All in all though, the most surprising role teashirt 3 has is, without a doubt, its connection with a newborn’s very first breath.

Indeed, very recently, researchers demonstrated that when teashirt 3 was deficient in mice, the rodents were incapable of taking their first breath and, as a result, died almost instantly. The reason for this is twofold. Seemingly, teashirt 3 has a direct role both in the opening and the shutting of upper airways, and the rhythmic heave of the lungs as they inhale and exhale. Under such circumstances, it is not difficult to grasp the notion that deprived of one of these events – or indeed both – a newborn has little chance of surviving.

In detail, with regards to the upper airways, teashirt 3 seems to be involved in controlled cell death of cranial motoneurons. To be sure, when teashirt 3 is deficient, motoneuron apoptosis is abnormally increased thereby tampering with the neuromuscular control for the flow of oxygen in the upper airways. How exactly this happens is still unknown but teashirt 3 may be important for the cell to cell signalling essential for the survival of embryonic motoneurons. It could be that teashirt 3 actually protects neurons from apoptosis. In the lower airways, teashirt 3 seems to be directly linked to the well-being of the chest pump. Without it, the respiratory rhythm generator (RRG), which governs the rhythmic contractions of the chest pump muscles, is disturbed. How is still unclear but it could have something to do with pH levels. When the umbilical cord is cut, unless there is a system to preserve the pH homeostasis, the RRG is not prompted. Hence the newborn is unable to breath.

This said, teashirt 3 cannot solely account for a newborn failing to draw its first breath. No protein acts on its own. However, teashirt 3 is certainly a key protein in the “simple” act of living. It is at the origin of our first breath and hence at the heart of our survival outside our mother’s womb. And it must surely have a decisive role in our very last breath too. Besides this knowledge, getting to know teashirt 3 more intimately may well help to prevent neonatal deaths, which remain for the great majority unexplained. And who knows? Perhaps, one day, teashirt 3 will help to prolong life by lending us that extra puff.

Noonan syndrome was named after Jacqueline Noonan, a paediatric cardiologist. Though the very first description of Noonan syndrome is credited to a certain Koblinsky, a medical student who attended the Russian Estonian University of Dorpat in the 1880s, Jacqueline Noonan was the first to notice that a rare type of heart defect in children was more often than not associated with short stature, a webbed neck, a wide space between the eyes and ears set lower than the norm. Her first paper on the condition was published in the early 1960s and it was the human geneticist John Marius Opitz, then a medical student where Dr Noonan had her practise, who suggested the term “Noonan’s syndrome”. Finally, the condition was officially named after the lady paediatrician in 1971.

If so many symptoms are the result of one protein, the said protein must be at the heart of an essential pathway which involves growth and development. Indeed, SHOC2 is part of the MAPK pathway which has a vital role in cell proliferation, growth, differentiation and migration. Many proteins are involved in the MAPK pathway which relays signals from the cell’s surface all the way to its DNA in the nucleus, switching genes off and on depending on the need and the moment. To meddle with such a pathway is sure to create chaos, and many forms of cancer are the result of such systems that have gone haywire.

"Human misery" by Paul Gauguin (1848-1903)

Source: www.paul-gauguin.net

SHOC2 is an in-between protein. It is neither on the cell’s surface, nor in its nucleus, but in the cell’s cytoplasm where it acts as a scaffold protein for two other proteins involved in the MAPK pathway: RAS and RAF. This does not come as a surprise since SHOC2 is made up of many leucine-rich repeats which are known to enhance protein-protein interactions. And which protein interaction does SHOC2 enhance? SHOC2’s role is to grab RAS armed with GTP and save it for RAF. The SHOC2/RAS duet then binds to RAF, and in so doing releases a phosphate, which in turn causes RAS and RAF to dissociate. The released signal phosphate continues further downstream, as it is transferred from protein to protein, until it reaches the nucleus and the cell’s DNA where it will activate – or indeed inactivate – the transcription factor of a given gene.

RAS and RAF are perfectly capable of binding to one another without the assistance of SHOC2 – but SHOC2, like a matchmaker, brings them together much faster so there is no delay in the pathway. So what happens to SHOC2 in the event of Noonan syndrome? One missense mutation in the SHOC2 sequence introduces a site for lipid modification known as myristoylation, which is irreversible. As a result, SHOC2 is rushed off to the wrong destination and, instead of being targeted to the cytoplasm to unite RAS and RAF, it is diverted to the cell’s plasma membrane where it remains. Consequently, the MAPK pathway loses its normal “dating service” regulated by SHOC2. The result leads to a perturbed MAPK pathway, and hence confusion in normal embryonic development which will result in the physical and physiological drawbacks specific to Noonan syndrome.

Naturally, SHOC2 is not the only protein which is implicated in Noonan-like syndromes. Other proteins involved in the MAPK pathway, and that are hindered one way or another, are prone to trigger off similar syndromes. The singularity of SHOC2 is that it is seemingly the first example of an acquired N-terminal lipid modification, in this case N-myristoylation, of a protein which actually causes a human disease – which is hardly a comfort for parents who discover that their child is suffering from congenital heart defects. However, a greater understanding of the role of SHOC2 will certainly help elucidate the ins and outs of the MAPK pathway which is central in the development of many cancers. In time, this will hopefully lead to the design of drugs that could reverse the effects of a protein which is sending off the wrong signal – a huge revenge on the tiniest of malefactors.