Dr Samuel Furse » THE LIPID CHRONICLES

 Fat is a Biological Issue Saturday, Feb 18 2012 

One of the first things we may notice when we meet someone new is whether they are fat or thin.  Equally, one of the first things we notice about people we know, but may not have seen for some time, is whether they have gained, or lost, weight.  The fact that the mass of adipose tissue can differ within an individual, and indeed fluctuate in their lifetime, is perhaps a clue to how our bodies store fats.

It is correctly well known that fats are a biological energy store.  In mammals, fats are stored in cells called adipocytes.  It is a useful adaptation to be able to store energy for use later, as it means that meals can be further apart and larger, if necessary.  Some species are much better at this than us, as demonstrated recently on a BBC documentary by Prof Richard Fortey.  Some species of turtle, and crocodiles, can survive for well over six months without a meal.  Indeed, this is an important factor in how their species survived a mass extinction event 65 million years ago in which their previous sources of food were compromised.  The ability of such cold-blooded creatures to reduce their calorific expenditure, by lowering their body temperature, is also a factor.  Although warm-blooded mammals such as humans would be hard-pushed to survive such an event if it happened today, we have at least adapted such that typically, missing a meal or even two, does not result in death due to starvation.

These observations beg questions about how fat is stored in our bodies, how it is stored in the bodies of metabolically efficient reptiles like crocodiles, and how our bodies release these stores of energy.  It would be no good if the stored energy were unavailable at the crucial moment.  Equally when the energy is released, it needs to be the right amount such that the individual can do what it needs to, without wasting those stores.

Mammals differ from plants in how fat is stored: in mammals there is one large fat droplet per adipocyte, whereas plants tend to use several, smaller stores. Adipocytes can be up to 120 µm wide, roughly 15 times wider than a sperm cell (8 µm) [1].  This enables them to store large amounts of fat in each cell.  This is part of the reason why, under normal circumstances, the number of adipocytes in a person does not change.  What changes if they gain or lose weight is the size of the fat store in each cell. The operation that removes some of the fat cells is called liposuction.

The vehicle for this storage of energy is the triglyceride (Figure 1).  Interestingly, this is exactly the same molecule used by plants for the storage of fat, and is the principal constituent of olive oil.  Triglycerides are moved around our bodies by assemblies called lipoproteins.  This means that when muscular tissue requires energy from fat stores, it can call upon that stored in adipose tissue, similar to the way that you can order your food shopping on-line and have it delivered to your house.

Once the fat arrives at the cells that will metabolise it, such as muscle or liver cells, the lipoproteins are taken up by the cells and place the fat in small reserves in the cell [2].  These are not convenient for long-term storage in muscle cells in particular, and so the vesicle that contains the lipoprotein is soon joined by another organelle called a lysosome.  This organelle provides the enzymes required for metabolising the proteins delivered, while the triglycerides are given over to mitochondria.  Mitochondria are responsible for turning the fat into energy and it is thus not for nothing that they are known as the power-houses of the cell.

Figure 1. Triglyceride, a molecule composed of three fatty acid molecules and one glycerol moiety. The blue sections represent the lipophilic part of this pseudo-lipid, where the red section is the most polar part of it. However, this polarity is insufficient to confer self-assembly properties on the molecule and thus it is a fat, rather than a lipid.

The chemical process goes by the unlikely-sounding Citric Acid Cycle (CAC), the discovery of which won Sir Hans Krebs a Nobel Prize in 1953.

You may be wondering where the atoms that made up the fats go.  Needless to say they are not destroyed by our bodies, so they must be dealt with somehow.  Figure 1 shows that fats are made up of carbon, hydrogen and a little bit of oxygen.  The hydrogen binds to oxygen, forming water that can either be lost in urine, or more usually, as water vapour in our breath*.  This is only part of the reason that heavier breathing is typical during physical exertion; the carbon from fats is turned into carbon dioxide that is also lost when we breathe out.

One last point about fats is that, like cholesterol, we can make as much of it as we need to.  Thus the nutritional requirement for fat is virtually nought, though they do have an impact on our enjoyment of a meal.  This adaptation indicates to biologists that a varied and not necessarily regular dietary intake was a significant factor at some point in human evolution: we have adapted to enjoy eating fats but can make all we need.

References and Further Reading

[1] B. Alberts, A. Johnson, J. Lewis, M. Raff, K. Roberts, P. Walter, Molecular Biology of the Cell, Garland publishing, 3rd edition, 0815316208.

[2] D. Voet, J. G. Voet, C. W. Pratt, Fundamentals of Biochemistry, John Wiley, 0471586201.

*We lose around 0•1 mL of water each time we breathe out. Based on breathing out once every 3 seconds, this means we breathe out just under 3 L of water each day.  Three or four urinations per day, of around 200 mL each, give rise to the loss of less than 1 L of water/day.

 

 

 When Plants Get Hormonal: Jasmonic Acid Thursday, Feb 9 2012 

Lipid synthesis is not always an end in itself.  While lipids and fatty acids are undoubtedly useful in themselves – for the formation of biological membranes and as signalling molecules in biological systems – they can also be a raw material for other processes. One such process is the preparation of the hormone jasmonic acid in higher* plants [1].

Plants are often not thought of as hormonal organisms and, while this is true for the simplest plants, more sophisticated plant species are reliant on a number of processes for survival, including growth in relation to sunlight and temperature and reproduction.  These processes can all be induced and controlled by the release of hormonal chemicals.  Jasmonic acid, like cholesterol-derived testosterone in mammals, typically has a range of effects on the plant. Under normal circumstances, it forms part of the development of the plant, including flowering and the formation of fruit.  Under stress, i.e., during a drought or after an injury, this hormone is part of the system that allows the plant to repair itself. But even that is not all.  Jasmonic acid is volatile (will evaporate easily), as is its methyl ester derivative (Figure 1).  The latter form, also found in plants and with similar activity to the acid, is also valuable in the perfume industry [2].

With such a variety of uses in higher plants (some of which are as important and quick as self-repair) speedy preparation of this hormone is required.  It is perhaps therefore not surprising that the raw material used to make this hormone is plentiful.  Plants use a fatty acid, called α-linolenic acid, to make jasmonic acid and its ester derivative (Figure 1) with the first stage of this process being the removal of the fatty acid from the membrane.  This starts with an enzyme called lipase that cuts up lipids.  In order for the hormone’s structure to be formed, oxidation is required to install a ketone and shortens the carbon chain from 18 carbons, to 10.  As you might imagine, these processes require several steps and thus several enzymes.

Figure 1. Jasmonic acid (left) and methyl jasmonate (middle), the methyl ester of jasmonic acid. The raw material for biological preparation of this hormone, α-linolenic acid (right).

The fact that several steps are required is perhaps more useful than it may sound, not least to the process of evolution.  It gives the opportunity for a huge range of mutations, and thus a huge range of changes and tunings of the system.  Not only does it mean that there is scope for variations of these two signalling molecules, but also the receptors with which they react can be more or less sensitive.  Perhaps not surprisingly, this has given rise to several related hormonal derivatives, such as jasmone [3].  This has led to an understanding of a variety of effects in plants, and lends growers a measure of control over the plants they cultivate.However, perhaps more elegant of all is the jump from the plant kingdom to the animal one.  The relationship between plants and insects is well established, with several insect species playing a crucial role in pollination.  Yet, in the case of a jasmonic acid derivative, it is the insects’ reproduction that is altered.  The hormone jasmone (Figure 2) is produced by the insect, a weevil called Bruchus pisorum, but can be detected by the plant, a member of the pea family, in breathtakingly low concentrations.  The plant is able to detect the hormone in what is known as the femto-molar range [4].  This means a limit of detection of 0•00000000000015 g of the hormone in 1 L of water.  To put it another way, the plant can detect this hormone, and thus the presence of the insect, at a level at which 1 Kg of jasmone is dissolved in a volume of water twenty times that of the Indian Ocean.

Figure 2. The structure of jasmone, a hormone that can be detected by members of the pea family at very low concentrations.

The effect of this hormone is to induce cell division and a strengthening of the plant’s its fibrous tissue.  This is something of a problem for the insect, as it means the larvae find it much more difficult to bite their way out of the plant’s tissue when they are fully grown [3].  So only the adult insects that produce both the larvae with the best eating action, and that emit the lowest amount of jasmone, are likely to survive.  However if the plant has no defence against this invading insect, it too will die out and the insect species will follow shortly after.  What is perhaps most exciting is that this indicates that the plant’s sensitivity to jasmone is helping to shape genetic changes in the insect population, and vice versa.  Needless to say, the struggle is not over – it never is with evolution – but it remains to be seen what will happen in the next stage of the relationship between the predator and the prey with respect to this lipid-derived hormone.

 

References

*This is the name given to plants that have a more complicated structure, including sexed plants (angiosperms), and so applies to trees and flowering plants, but not algae.

[1] R. A. Creelman, J. E. Mullet, Proc. Natl. Acad. Sci., 1995, 92, 4114-4119.
[2] M. Hamberg, H. W. Gardner, Biochem. Biophys. Acta, 1992, 1165, 1–18.
[3] H. Weber, Trends Plant Sci., 2002, 7, 217–224.
[4] R. P. Doss, J. E. Oliver, W. M. Proebsting, S. W. Potter, S. R. Kuy, S. L. Clement, R. T. Williamson, J. R. Carney, E. D. DeVilbiss, Proc. Natl. Acad. Sci., 2000, 9, 6218-6223. http://www.pnas.org/content/97/11/6218.short

 

 Lipids – Where Do I Go? Thursday, Feb 2 2012 

Research is a notoriously vague occupation. It has more in common with gathering than hunting, and so inevitably has as much support as opposition. Researchers of all types will probably tell you that there is no substitute for putting the hours in and, of course, knowing where and how to look. These skills are undoubtedly useful when wanting to find more information on a subject as wide as lipids. In researching something in the 21st Century, our first port of call is typically Google, or, when in dire straits, an on-line encyclopaedia that is best left unnamed. As a source of information on lipids I cannot speak highly enough of this blog of course, but even it cannot contain everything. So, what if you need to go further?

There is a huge wealth of what is known as primary literature. These are original research papers that have been published in peer-reviewed journals*. What this means is that a scientist, or more usually a group of scientists, has written up some experimental work typically in a format of several sides of A4 long. This is submitted to a scientific journal, who send it to anonymous reviewers, who then send back comments. Assuming that the reviewers are not out of their depth, and the authors are professional about the process, the manuscript will be modified by the authors and resubmitted. If it is then thought suitable, it is accepted for publication. A large number of articles are accepted every month, these are published in sets (issues). As one may imagine issues are bound together to make up volumes.

The wealth of information in the primary literature is undoubtedly a hugely important one. It is often not necessarily difficult to find journals that are focussed on lipids; indeed there are a number focussed in this area, but there are some limits to this source of information. Unfortunately, such journals can be difficult to obtain access to if readers are not members of subscribing institutions (Universities etc.). Additionally, finding the right papers can be difficult for non-specialists: it is as easy to get bogged down as it is to miss crucial works. A more readily accessed, and smaller body of work, is the secondary literature.

Secondary literature is the term commonly used to refer to books on a given subject. A quick search on Amazon readily reveals the abundance of lipid literature that is available. Inevitably some titles can be picked up for almost nothing, a nominal £0.01 plus postage, and can allow one to put together a library of sorts on this subject with little effort. Although they are mostly titles resulting from investigative analyses of fat or lipid components of food – trans fats, cholesterol and so on – they provide a source of practical information. Others are perhaps a bit less scientific – for example, some seek to draw a distinction between good and bad fat, and another that appears to purport the belief that lipids form an important part of slowing the ageing process.

There is much in the mid-range but if you are feeling rather rich, educational and scientific books about lipids with much smaller print runs, but much more reliable information, are also available. At current prices, a little over £800 can buy you a copy of Lipid Research Methodology from 1984. Although now probably superseded in all principle tenements, it provides a good historical view of lipid chemistry. A newer book for a mere snip over £900 is The Chemistry of Oils and Fats. If you feel you have more spare money than can be sated by even those, around £1,700 can buy you a treatise on lipid microbiology and for a little more than £3,000 a thorough guide to the mass spectra of lipids is available (!).

You may be comforted to know that few lipid chemists have any such titles, either in the laboratory, or at home. Larger scientific reference libraries may do better, but as the subject of lipids is wide, taking in aspects of biology, chemistry and physics at least, you may prefer to find the right person to ask, instead. And you will be pleased to hear that Google is as good for that as anything else.

 

*Although non-peer reviewed journals are available, these typically have little value in scientific circles as the work published is not subjected to the rigorous scrutiny afforded by peer-reviewed journals to their issues.

 

 At the Mercy of a Ganglioside Thursday, Jan 26 2012 

We never think of our own bodies as toxic, but for some people they can be, and this sad fact of reality often only dawns slowly. This type of illness can be understood in terms of a recognition problem between proteins.

Problems of the body finding itself toxic are also observed in lipid-containing systems. Our understanding of a genetic condition called Tay-Sachs disease (TSD) is based upon evidence relating to a failure to break down certain lipids called gangliosides. A build-up of gangliosides causes the symptoms of the disease, which becomes evident in the first few months of life (Stryer, 2000). As this condition is genetically determined, without a change to the genetic structure of the individuals concerned, only a treatment of the symptoms is feasible.


Figure 1. The inheritance of dominant (top) and recessive (bottom) genetic conditions. If a trait is mediated by a dominant gene (D), statistically half the offspring will develop that trait. If it is mediated by a recessive gene (d), both parents must carry the gene in order for only one in four to develop it, however two in four offspring will carry it.

The genes that cause TSD are recessive, meaning that the condition is only observed in an individual if both parents carry the recessive gene (Figure 1), such that a recessive copy from both parents is inherited. The chances of acquiring a recessive genetic condition are therefore one in four under these circumstances. Additionally, if both parents carry the recessive gene in their genotype, two in four (one in two) of the offspring will also carry the gene (but not suffer the disease). If only one of the parents carries one recessive copy, statistically none of the off-spring will develop the condition*. . The only way a child could develop the condition under those circumstances was if a serious mutation occurred, leading to two copies of the recessive gene being present.

TSD is also known as GM2 gangliosidosis. This is because the condition centres around the breakdown of ganglioside GM2, a lipid found in nerve cells (neurones, Figure 2). In TSD, the ganglioside is not broken down and so it builds up in lipid-storage organelles in cells, called lyposomes (Figure 3). The failure of the ganglioside to be broken down, is caused by the absence of an enzyme called β-N-acetyl hexosaminidase. The build-up of ganglioside GM2 that then occurs causes cells to die (Stryer 2000). GM2 gangliosides are particularly common in the nerves of the brain and spinal cord and so when those cells die, the symptoms of the disease are observed through changes in the behaviour of those systems.


Figure 2. The molecular structure of one of the gangliosides that sufferers of TSD are not able to metabolise (break down by hydrolysis)

The absence of the required enzyme is a result of mutations or errors in something called the HEXA gene (NCBI website, 2012). This means that the enzyme is not synthesised in the same way as it is in unaffected individuals during protein synthesis. This is because amino acids in the primary sequence are missed out (causing a frame shift), or are replaced with others. This means that this globular protein does not fold up properly and so the active site in the normal β N acetyl hexosaminidase does not form, causing the catalytic activity of the protein to be either drastically reduced or entirely absent.


Figure 3. An electron micrograph of spinal cells from a sufferer of Tay-Sachs disease, Nelson & Cox, Lehninger Principles of Biochemistry. This picture shows the enlargement of lyposomes (by a factor of 100) on accumulating gangliosides.

The clinical symptoms of TSD include muscle weakness and poor muscle co-ordination (ataxia). The combination of these means that normal movements, such as crawling and turning over, stop before the child is a year old. The patient quite literally is unable to move him or herself; the nerves connecting the brain to the muscles just do not work. After this time, nerve function is reduced still further, causing sufferers to go blind and deaf. There is also a characteristic formation of spots on the eyes that are cherry-red, which is a symptom unique to this condition and is taken as a strong diagnostic sign. Paralysis is also common in the latter stages of the disease, before death. Death normally occurs before the age of 3 years (Desnick and Kaback, 2001). The condition is thus very serious and the opportunity for care is basically absent.

There is a form of TSD that appears more slowly, though this is rarer than the usual form. This is known as late-onset Tay-Sachs disease. The same symptoms are evident, by their progress is a good deal slower than in the more common (infantile) form. The cause in this case is too little of the enzyme to break down the ganglioside effectively. This arises because of a fault with the gene that regulates the synthesis of β-N-acetyl hexosaminidase from the HEXA gene. Another possibility is that the enzyme that is produced is only slightly mutated and so it does have some catalytic activity but that this is much less than the healthy form.

It is now possible to diagnose the condition during pregnancy, where a sample is taken and tested for activity of the enzyme. If there is little or no activity, it is asserted that the enzyme is absent and that the child has the condition. Statistics from America suggest that, in that country, about 3% of Jews originally from eastern Europe (Ashkenazi) carry the disease, with only 0•03% of the general population being carriers (Stryer 2000).

There are also ‘pockets’ of the condition elsewhere in North America, with evidence for it in communities in Pennsylvania, Louisiana and Quebec (Desnick and Kaback, 2001). As the number of carriers of the condition is relatively low, and so closer-genetic breeding (such as first- and second-cousins) is required for the chances of two carriers to be statistically likely, the impact of this condition is low. However, the effect of the principle form of the disease (infantile-onset) on the individual is clearly severe, and thus heartbreaking for the family. The occurrence of the condition in a child will raise the question of which other children of those parents may be affected, and how further pregnancies should be managed.

Religious belief may also influence this. In Jewish religious law, there is not a clear policy on abortion and so parents of Ashkenazi Jewish extraction may be able to abort pregnancies in which the foetus has Tay-Sachs disease. However, prospective parents in places such as Pennsylvania and Louisiana may not be able to do so, as much of the United States of America is decidedly anti-abortion. Thus in the few cases where babies are born with this condition, questions about the compassion amongst an anti-abortion approach may be raised.

Current medical thinking suggests that the only feasible option for dealing with both of these conditions is through preventative medicine. This means that clinicians and physicians use strategies and methods to prevent the disease occurring or starting, rather than trying to change it (management) or undo it (cure) once it has started. Although this would clearly be effective, and prevent disease occurrence, unfortunately it raises a variety of ethical questions for religious people, particularly Christians, who find themselves unable to exert any personally-driven influence on the process. This is particularly relevant for TSD, which occurs in strongly protestant communities in parts of the USA (Louisiana, Pennsylvania). Such steps include screening pregnancies for the conditions. Another option is fertility treatment in which several ova and the resulting embryos are screened for the condition(s) and those found to have it are discarded, ensuring that the condition does not propagate to the offspring but that they are ‘their’ children. Aborting pregnancies in which the condition(s) have been detected is also an option, though the prospect of this is quite emotionally, as well as religiously, difficult.

Despite this, the study of these conditions has produced a good deal of understanding of both the conditions themselves but also about genetic inheritance and the effect of neurological disorders, both short- and long-term, on the body. Without a concerted effort to avoid these conditions through preventative measures, the conditions will never disappear altogether. Additionally, further random mutations may occur, leading to a re-emergence of these diseases, or ones that closely resemble them.

References and Notes

* This method of recessive inheritance is also how ordinary traits such as eye and hair colour are inherited.

L. Stryer – Biochemistry, Fourth edition, 2000, 0716720094

Tay-Sachs Disease, Ed. Robert Desnick, Michael Kaback, 978-0-12-017644-1, Academic Press, 2001.

Further Reading

NCBI reference website, http://www.ncbi.nlm.nih.gov/books/NBK22250/ (accessed January 2012)

 

 How Hot is Hot? A Burning Question About a Hot Condiment Thursday, Jan 19 2012 

Plenty of people like a good hot curry. I am not one of them, but I think that most people have met, or know, someone who likes wolfing down the hottest curry in the house as a matter of pride. I do know someone who likes to munch on the same kind of hot curry but exquisitely slowly. Either way, it is safe to assume that pretty much anyone who has had a strong curry, and either enjoyed it or not, will remember the flavour forever.

There has even been a certain amount of study on this topic: some time ago, the compound capsaicin (Figure 1) was identified as the cause of the hotness. Several related compounds have also been identified, some of which are ‘hotter’ than others. This led to the desire to measure the ‘hotness’, resulting in the Scoville Heat Unit, and the Scoville Scale.

There is also the well-known opportunity for a schadenfreude with curry flavours. As it can be a strong flavour, when someone bites on something unexpectedly teeming with chopped jalepeños, the shock on their face is palpable. However, this shock can also be turned on its head with respect to public order. Recent anti-capitalist protests in America have given rise to some disturbing images of people sprayed with a capsaicin formulation (commonly known as pepper spray) either intentionally, or apparently not.

While these are shocking, and the mental and physical distress caused by the use of this ‘riot-control agent’ are readily understood, other factors are also important. The use of pepper spray as a weapon of self-defence, against a rapist or criminally violent attacker for example, seems not unreasonable. However, the link between pepper spray and deaths in people exposed to it who also have compromised respiratory function, increases the interest in managing the use of pepper spray, both politically and scientifically.

Figure 1. The structure of capsaicin, showing a more polar section (left) and a more lipophilic one (right), giving rise to a comparison with lipid structures.

One way of taking things further is to understand the science behind what is happening when pepper spray is used. A judgement can then be made about safety and appropriate conditions for use. The structure of capsaicin (Figure 1) suggests that it has a lot in common with what we know about lipid structure – a relatively polar (hydrophilic) section as one end, and a lipophilic hydrocarbon chain as the other. However, it is not just the lipid-like properties of capsaicin and its related compounds that give rise to the effect we remember so readily – after all, we eat lipids of one sort or another in almost every mouthful and most do not have the same effect as a vindaloo on our taste buds. This hot sensation is due to an effect of the capsaicin on nerves that feel heat (thermoception) and pain (nociception).  Recent work has suggested that there is a direct impact on the activity of calcium channels in nerves and earlier work has found that such exposure was responsible for permanent damage to the cells involved.This is quite sobering when looked at from a riot-control angle. If a chemical is able to cause innervation, as measured by pain, it is arguable that it is a drug. If it is a drug, strict licensing laws would apply. This also influences the dose(s) that can be used legally. Perhaps we need to reflect on the use of pepper spray of indiscriminate dose, as a crowd control agent?

 

 Suet: A Protective Subject Thursday, Jan 12 2012 

It all started with a Tweet. “Are you watching Only Connect?  There’s a round about lipids” came the missive from an excited lipid-watcher.  To my lasting regret, I was not in front of BBC2 at that moment.  I did however catch it on iPlayer a day or two later.  The round included sunflower oil and suet.  The latter was the one that stood out to me.  Suet is something I had heard of as being in pastry, and definitely in mince pies, so I was sure it did actually exist, but wanted to pin down why it was grouped with things like olive oil and sunflower oil.

My first port of call was the bookshelf.  Michel Roux’s book ‘Pastry Savoury and Sweet’ makes no reference to suet, and perhaps more surprisingly, neither does my concise Larousse Gastronomique.  Delia makes just one reference to it in her Complete Cookery Course, as an ingredient in savoury pastry, but this is not quite a treatise on what suet is.  What she does say, is that it is a heavy fat from beef.  Although this is by no means wrong, lipid chemists would refer to it as a saturated animal fat, mainly composed of stearic acid.  More specifically, the suet sold in supermarekets is actually pebbles of fat that have been caked in wheat flour in order to stop them sticking together.

But where it comes from is a bit more gruesome: it is the fat used by the bodies of cattle, sheep and pigs to cushion abdominal organs such as the kidneys. When it is first removed from a carcass, it is therefore a sort of white lump.  However unpalatable this may seem on the face of it, in order to make our own bodies properly, similar materials are useful to us.

As all ardent bakers will know, is impossible to make pastry without a source of fat. Generally this is butter, and just occasionally it is from another source.  For savoury pastry, such as that in a esteak and kidney pie, it is seen as ideal as it goes well with these flavours.  Beef dripping can also be used, but this is the fat from beef that has been cooked.  However, as this is liquefied, it will have lost some of the constituents that would otherwise be in suet, such as the protein.

So, we have our answer. Suet is indeed not really a lipid, but a fatty isolate from raw animal carcasses.  It is also typically as fatty as olive oil, but, as it is saturated fat, it is a solid at room temperature.  That makes it a bit tougher than oil, and actually tougher than butter too, and, as anyone who has rolled several types of pastry will know, that makes it easier to roll out.  Also, the fact that it is a solid at room temperature means it can give a thicker texture to foods such as mincemeat.  No wonder it has been used for hundreds of years for making the perfect pie.

 

 Bending in Two Different Directions at Once Saturday, Jan 7 2012 

Have you ever tried to bend a piece of paper in two different directions at once? If not, try it with a piece of paper about 5 cm by 5 cm: hold the sheet of paper in front of you, bend the top left and bottom right corners up, and the other two corners down (Figure 1, left and centre). You may need someone else to help you, but either way, you will quickly find that it is impossible to bend the piece of paper in this way without it either tearing or creasing. This is in contrast to the effect of bending the paper across its middle, i.e., bending it when holding the two pairs of adjacent corners, where it happens readily and without tearing (Figure 1, right).

Figure 1. Diagram of the effect of trying to bend a square sheet in two different directions simultaneously (left and centre). Does it work with a sheet of paper?

It is easy to imagine that the first kind of bending, the one that tore or creased the paper, will work better with a flexible material such as rubber.  It is also obvious why: the rubber can stretch, it is elastic.  Paper lacks this quality, and as the applied force overcomes the forces holding the sheet together, the sheet breaks.  We know that bilayers are sheets, and so this begs the question ‘What happens when we try to bend a sheet of lipids?’

It would obviously be useless if the lipid bilayer were like the sheet of paper: moving your hands to type, or moving your eyes to read this sentence, would result in the rupture of many millions of your cells.  That does not have an evolutionary advantage and so, by this stage in cellular evolution, it no longer occurs.  Nature has developed a way of ensuring that cells have a measure of flexibility in their membranes to cope with applied forces.  This includes forces from within the body, such the pressure between forearm and upper arm, of folding an elbow, or peristaltic activity in the small intestine.  It can also be external ones such as air, or water, pressure.

Figure 2. Left, cell division at the stage shortly before membrane fission. Image courtesy of Harold C. Smith, University of Rochester, Rochester, NY, USA. Right, unduloid surface analogous to that observed in vivo, with curvature in opposite directions simultaneously, shown here in a repeating manner. Image courtesy of David Dumas, University of Illinois at Chicago (2010).

Figure 3. Left, saddle shape shown on a leather dressage saddle, with the curve that is perpendicular to the plane of the paper shown in white. Right, saddle formation of the lipid molecules, where the curvatures are at perpendicular planes (J. M. Seddon, R. H. Templer, 1995, Polymorphism of Lipid-Water SystemsfromThe Handbook of Biological Physics, ed. R. Lipowsky, E. Sackmann, Elsevier Science). Points: (a) Saddle point or seat, i.e., where the two curves meet and there is curvature of both negative and positive sign at once (In practice this is restricted to no more than one lipid molecule), (b) Left (arbitrarily assigned name) apex of the upper curve, (c) Right apex of the upper curve, (d) and (e) are the apices of the lower curve.

Clearly there are limits to what we can endure. Other species have different adaptations, however.  Anybody who likes penguins will know that they are quite happy with the (air) pressure on land, but also can dive and swim at considerable depths in the sea.  This is a huge range of pressures, and it is not an accident that penguins are adapted for this breadth of conditions.  The physical requirements are not just for strength, e.g., to breathe despite the external pressure, but also for physical resistance to pressure at a cellular level.

Although this may seem unexpected, there is more (and in my opinion this is the most interesting bit).  Whilst we understand how the cell membrane is constructed (well beyond the point of knowing that biological membranes are not flat), and what a membrane does, we also know that in order for you to be reading this now, millions upon millions of cells have had to reproduce, fight infection and communicate with one another.  And that is just in your body, carries on all of the time and hopefully without your being aware of it.

What all these processes have in common is that they involve membrane-dividing, or membrane-fusing, events as a crucial stage.  And all of these things must occur despite applied pressure, and changes in this applied pressure.  There is no evolutionary advantage to forcing a penguin to stand still for a while, such that its cells can divide without changes in pressure.  So how does the body do it?  Well, there are several things, not all of which are lipid-based.  Mammals and birds have a skeleton, which helps give support to the whole body. Although not the full answer at a cellular level, it is undoubtedly a helping hand.  At a lipid level, the rest mainly consists of enzyme (protein) action causing changes in the desired shape of lipid molecules.  So, if the action of an enzyme means that a lipid is no longer cylindrical, but wedge-shaped, the thermodynamic driving force for bending the membrane will start to emerge.  This can be particularly intricate, and can even be responsible for driving the membrane to bend in two directions at once (Figure 2).

A surface bending in opposite directions simultaneously is described as having negative Gaussian curvature. Despite its obscure-sounding name, the concept of something flat bending in two directions at once is not unique to cells.  Figure 3 shows an example of this, the seat of a saddle. A bilayer can be draped over the same shaped surface in order to give this shape.  Cells exploit this topology as an intermediate in division (Figure 2).  Not only does the cell exercise control it for this process to occur, but it does it despite external pressures, both internal, and external.

 

 Olive Oil: A Great Swindle…That Wasn’t Saturday, Jan 7 2012 

As a geeky teenager, I used to read the nutrition information labels on foods for entertainment.  Early on, I noticed a few things that sounded somewhat peculiar out of context.  For example, I was stuck by how difficult it was to guess what a food was from its nutrition information.  This worked both ways though: what foods had in them was quite difficult to guess just from knowing about them.  Years later I realised that this is the sort of thing that some food scientists work on.  I learnt that we have ended up thinking that water is the healthiest food around, chiefly because it has nothing in it.  I also saw that olive oil is only ninety-something per cent fat.  Sugar, on the other hand, is a full one hundred per cent carbohydrate.  Health benefits aside, I was immediately intrigued by this revelation.  (a) Why was something called ‘oil’ not completely oil, and (b) How could manufacturers get away with olive oil not being the full monty? Looking at different bottles, to see whether it was just that one I found out that some were 85% fat and some were more like 95%.  This prompted my third question (c) Why did it vary so much? The difference between 85 and 95% at is a bit of a shift for something that has the same name.

It was my first inkling that both marketing and food scientists had a lot to answer for.  However, the drama was moot in any case: TV chefs rattled on as much about good ingredients then as they do now, and cheap stuff was not as good as expensive stuff then either–so the chances were we were not being duped on a big scale.  The question remained though: What is the stuff in olive oil that is not fat?  What we need to do to answer this question is a bit of scientific analysis.

Nuclear Magnetic Resonance (NMR) Spectroscopy tells us that the dominant compound in olive oil is a triglyceride made, mainly, of unsaturated fatty acids. A typical triglyceride is shown in Figure 1.  One of the other ways we know it is a triglyceride, and the method used before NMR was invented, is by studying how it reacts with other chemicals.  Specifically, if one part triglyceride reacts with three parts of potassium hydroxide, to give three parts fatty acid and one part glycerol, it was seen as bona fide triglyceride.

Figure 1. The saponification of a triglyceride (top), giving rise to glycerol (bottom left) and three moles of fatty acid (bottom right).

 This reaction (Figure 1) is also the key to why olive oil is only ninety-odd per cent fat – apart from the green colouring. A calculation of the molecular masses tells us that glycerol represents around 10% of the mass of triglycerides, which is not a fat. This is why olive oil is not 100% fat. Expert bakers will tell you that glycerol, also known as glycerine* is quite sweet to taste and dissolves in water. It is also used to stop icing becoming dry and brittle. It is thus not a fat, and so is not listed under the fat content on the nutrition information.

When I realised this, I was a bit surprised at my original view. My reaction to the contradiction I first saw had been turned inside out. Now I know that olive oil that does not have 100%, or nearly 100% fat in it, because it is principally composed of triglycerides rather than fatty acids.  As this means it has probably seen less processing than other foods, it is therefore likely to be of a better quality. This also reflects well on the materials used to make it, because good olive oil does not need to be processed at all.

*Also used to make nitro-glycerine, the explosive that is in dynamite. 

 

 Biological Signalling Thursday, Dec 22 2011 

The approach of determining the lipid composition of living systems, called lipidomics [1], has demonstrated that a huge number of lipids are present in living systems.  Recent publications showing this in sharp focus include reports of the complete lipidome of part of the murine (mouse) immune system [2] and human plasma [3].  What this work shows, is that there are over 500 distinct molecular species distributed amongst the established lipid categories.  Reasoning would suggest that this is a large number of lipid types for the physical job of producing a cellular membrane (despite the need for several types of lipid in order produce a cellular membrane).

This begs the question: what are the remaining lipids for?  It is tempting to believe they have no function, however evolution suggests that this possibility is unlikely in nature, i.e., what evolutionary advantage would there be to produce lipids that are of no use?  What is far more likely is that there is a function.  And indeed this turns out to be the case.

Several of the minor lipid components of these systems are known to be biological signals.  Inositides are the dominant example of this.  One member of this group, called PIP3, forms part of the system that manages the release of insulin from the β-cells of the islets of Langerhans [4].  However, there is also much evidence [5] that PIP3 is also involved in the activation of a protein called PKB.  This protein is an enzyme that phosphorylates other proteins, activating them.  Enzymes that phosphorylate are called kinases, hence PKB: Protein Kinase B.  This enzyme, or more specifically, the phosphorylation it performs, is at the heart of the body’s control of growth.  It is therefore similar to the sort of signalling systems that go wrong in diseases such as cancer.

The research into PIP3 has been seen as important, and the development of an understanding arising from them, significant. This lipid has even been prepared using synthetic organic chemistry [6], such that sufficient stock of this lipid is available for further research. However, the fact that this lipid has proved to be so important in biological systems has made the other seven inositides rather more attractive than they once were. Thus, attention is now turning towards them. Phosphatidylinositol itself is the precursor to all other inositides. Kinase activity similar to that elicited by PKB turns phosphatidylinositol into inositides such as the phosphatidylinositol phosphates. There are three types of phosphatidylinositoldiphosphate head group, but only one phosphatidylinositoltriphosphate. Although no signalling role has been discovered for phosphatidylinositol, what has been discovered is that it can have a pronounced effect on the curvature of the lipid system of which it is part [7].

The demonstration of a pronounced effect on membrane curvature and an important biological signalling role for lipids that are closely related chemically is a bewildering thought. Are inositides an unappreciated force in vivo?

References

[1] E. A. Dennis, Proceedings of the National Academy of Sciences, 2009, 106, 2089–2090. http://www.pnas.org/content/106/7/2089.full.pdf+html?sid=e68904de-d625-41e0-aa17-cc9a36be94c2

[2] E. A. Dennis, R. A. Deems, R. Harkewicz, O. Quehenberger, H. A. Brown, S. B. Milne, D. S. Myers, C. K. Glass, G. Hardiman, D. Reichart, A. H. Merrill, M. C. Sullards, E. Wang, R. C. Murphy, C. R. H. Raetz, T. A. Garrett, Z. Guan, A. C. Ryan, D. W. Russell, J. G. McDonald, B. M. Thompson, W. A. Shaw, M. Sud, Y. Zhao, S. Gupta, M. R. Maurya, E. Fahy, and S. Subramaniam, Journal of Biological Chemistry, 2010, 285, 39976-39985. http://www.jbc.org/content/285/51/39976.full.pdf+html?sid=1a75f1d7-9661-4fc8-af76-cd29dd1cc326.

[3] O. Quehenberger, A. M. Armando, A. H. Brown, S. B. Milne, D. S. Myers, A. H. Merrill, S. Bandyopadhyay, K. N. Jones, S. Kelly, R. L. Shaner, C. M. Sullards, E. Wang, R. C. Murphy, R. M. Barkley, T. J. Leiker, C. R. H. Raetz, Z. Guan, G. M. Laird, D. A. Six, D. W. Russell, J. G. McDonald, S. Subramaniam, E. Fahy, and E. A. Dennis, Journal of Lipid Research, 2010, 51, 3299-3305. http://www.jlr.org/content/51/11/3299.full.pdf+html?sid=a1eb540d-d814-47ad-b102-455aeb3852b2

[4] O. I. Hagren and A. Tengholm, Journal of Biological Chemistry, 2006, 281, 39121-39127. http://www.jbc.org/cgi/doi/10.1074/jbc.M607445200

[5] B. A. Hemmings, Science, 1997, 277, 534. http://www.sciencemag.org/content/277/5325/534.full

[6] P. R. J. Gaffney and C. B. Reece, Journal of the Chemical Society, Perkin Transactions 1, 2001, 192-205. http://pubs.rsc.org/en/content/articlelanding/2001/p1/b007267m

[7] X. Mulet, R. H. Templer, R. Woscholski and O. Ces, Langmuir, 2008, 24, 8443–8447. http://pubs.acs.org/doi/full/10.1021/la801114n.

 

 Lipidomics Thursday, Dec 15 2011 

One of the big questions in biology is how living organisms work. How do we stay alive?  Understanding of this over the last two centuries has led to the development of science into the chemistry that sustains life in biological systems.  This is what biochemistry is.  A recent approach to understanding living systems has been to work out what all the genes are in a given organism.  This is all the genome is: all the genes an organism possesses.  Knowing what the genes are is useful because it tells us which proteins can be made. These proteins go on to do a variety of things, like speeding up digestion (enzymes), or for making the machinery required for cells to control what passes through their membrane (e.g. ion channels, which you may have read about here).  Genes and cataloguing the genome is an important advance in science, but it does not tell us everything. 

It is also useful to understand the range of other components present in a system, such as the lipids.  Knowing the complete lipid profile, the lipidome, of a system is particularly informative.  The word lipidome may seem unfamiliar, but it is the lipid equivalent of the genome in genetics, that is, a catalogue of every lipid in a given species. 

Once we know which lipids are present, and how much, we can use published evidence of the individuals’ behaviour to make conclusions about the relationship between what we observe in vivo.  Physical evidence from biophysical studies, such as the use of x-rays to determine the topology of the self-assembly in lipid systems [2], is also used to inform the understanding of these systems.  Lipidomics [1] is a relatively new approach to understanding the lipid fraction of biological systems.  In physical terms, it allows us to re-construct the system from the known behaviour of its parts. This is a more fundamental approach that is perhaps superior than simply doing things to lipid systems to find out what happens, such as adding chemicals that disturb the forces that hold lipid systems together.  Such chemicals are celled chaotropes [3,4,5]. 

Lipidomics sounds remarkably easy. We know what we need to do, and there are just a couple of steps to achieve it. We have a problem, however. Isolating these lipid molecules is more difficult than for proteins or DNA. Certainly adding solvents to dissolve the lipids makes sense, but this is awkward if we consider the relationship lipids have with water, and particularly so if they are more like a surfactant (i.e. soap) than a lipid.  This has not stopped tenacious lipid chemists from using sophisticated solvent systems to extract lipid fractions from plant, animal, or fungal material [6], however.  But this on its own is not enough.  Current lipidomics methodology also uses mass spectrometry to identify the molecules according to their molecular mass.  If this is accurate enough, it can be used to determine the number and identity of the atoms present.  This in turn is used to pin down the lipids’ identity. 

If this approach is applied to a whole organism, such as Saccharomyces cerevisae [6], the species of yeast used in baking bread and making beer, the results produce a lipidome of that species.

The lipidome tells us about the range of lipids the system is capable of producing, and does produce, which then informs us about the range of physical behaviour of membranes in the system.  The most exciting thing about this, in my opinion, is that we might then be able to understand the role of lipids in cell division.  How we get from one cell membrane to two is a physical process, but without an understanding of the lipid component we cannot construct a picture of how this happens on a molecular level.  Once we do, the understanding of lipids in a system will be at the same level as that of DNA and proteins.

References

[1] M. R. Wenk, Nature Reviews, 2005, 594, 594-610. http://staff.washington.edu/mwhiddon/Wenk%20et%20al.pdf
[2] X. Mulet, R. H. Templer, R. Woscholski, O. Ces, Langmuir, 2008, 24 , 8443–8447. http://pubs.acs.org/doi/abs/10.1021/la801114n
[3] K. Kinoshita, M. Yamazaki, Biochimica et Biophysica Acta, 1997, 1330, 199-206.
[4] G. C. Shearman, S. Ugazio, L. Soubiran, J. Hubbard, O. Ces, J. M. Seddon, and R. H. Templer, Journal of Physical Chemistry B , 2009, 113, 1948–1953. http://pubs.acs.org/doi/abs/10.1021/jp807998d
[5] Y. Feng, Z. W. Yu, P. J. Quinn, Chemistry and Physics of Lipids ,
2002, 114, 149–157. http://www.kcl.ac.uk/kis/schools/life_sciences/life_sci/quinn/publications/cpl114.pdf
[6] C. S. Ejsing, J. L. Sampaio, V. Surendranath, E. Duchoslav, K. Ekroos, R. W. Klemm, K. Simons and A. Shevchenko, Proceedings of the National Academy of Sciences, 2009, 106, 2136-2141. http://www.pnas.org/content/early/2009/01/27/0811700106 .

 

 Curvy Biology Friday, Dec 9 2011 


There is no such thing as a straight line in nature. This is especially obvious in cells and in their membranes. The absence of straightness from biological systems, including that of bilayers, presents a problem for membrane biophysicists and lipid chemists. Although the principles governing the way the lipid molecules used by cells to make membranes are well understood for flat bilayers, the presence of curvature provides an additional dimension to what we see. However, as with a lot of science, it gets a little bit more complicated before it gets simpler.


Figure 1. Curvature in membranes. (a) Prostate cancer cell, taken by Robyn Schlicher of Georgia Institute of Technology, showing normal curvature of all membranes; (b) A bilayer of phosphatidylcholine, showing that this lipid cannot form a curved surface as this would require vacuums in between the lipids; (c) The inclusion of cone-shaped lipids into a PC bilayer allows the layers to produce a curved surface without a vacuum.


Figure 2. Curvature in membranes arises through lipids of differing shapes. Left is the type II phosphatidylethanolamine, that gives rise to negative curvature. In the middle is the type 0, cylindrical, phosphatidylcholine that does not induce any curvature. On the right is lyso-phosphatidylcholine that brings about positive curvature in membranes.

The bilayer of lipids that makes up the plasma membrane is constructed of two mono-layers that face in opposing directions. Thus in order for the bilayer to bend, the mono-layers must bend in opposite directions in order that the bilayer bends as one entity and does not form a vacuum in between the mono-layers (Figure 1a). Mathematicians will say immediately that this means the leaf on the inside of the bend* has a smaller surface area. So, with a smaller surface area, why does the cell not have fewer lipids on the inside than on the outside? The answer is that it does, but that this is not enough to bring about curvature on its own, as there would still be gaps (Figure 1b). This problem is solved by the cell having lipids that are of different shapes (Figure 1c).

We are familiar with lipids that produce flat bilayers, such as the phosphatidylcholines, including Dioleoylphosphatidylcholine (DOPC). These are called type 0 lipids. There are also type I lipids, and type II lipids (Figure 2). Type I lipids include a modified form of DOPC, in which one of the fatty acid residues has been removed. This is known as lyso-PC. This is type I rather than type 0 because the choline head group is larger than the greasy hydrocarbon fraction, and so the lipid forms a cone shape. This cone shape means the lipid’s presence in a bilayer encourages positive curvature – curvature away from the water. This is useful to the spheroid cell, as the outside of its membrane can curve away from the water. This is complimented by type II lipids, in which the fatty acid part of the lipid molecule is wider than the head group. As we cannot bolt another fatty acid residue onto PC to make it type II, we can instead modify the head group to make it smaller. This gives rise to an entirely different type of lipid, called phosphatidylethanolamine.

So, with just these three lipids, we can bend a lipid monolayer in either direction. If they were arranged around something, they could even form a textured, or curvy, surface. Mitochondria, the powerhouses of the cell, need a large membrane inside as this is the surface required for many of their chemical reactions to take place. This inner membrane requires the presence of all three of these types of lipid in order to bend into flaps to give itself this large surface area (Figure 3). This, however, is not the full story. Although further work has been done, exactly how the membrane changes and its dynamic nature through processes such as cell division are not yet fully understood.     


Figure 3. Curvature in membranes in the mitochondrion; , shown in both an electron micrograph, and a drawn diagram. Image from Brooklyn College City University of New York
 


Notes

* In in a cellular system, bending towards the water is known conventionally as negative curvature.

 

 A Long Name, a Long Lipid: Docosahexaenoic Acid Friday, Dec 2 2011 

It is often difficult to get a handle on what molecules are and what they do. In biological systems, there are many that carry out and are involved in several unrelated processes, as we have seen with cholesterol. This means the work that scientists need to do to uncover a molecule’s true importance usually requires contributions from several scientific disciplines. However, cholesterol does not quite fall into the category of the molecule I want to discuss here, because unlike cholesterol, we cannot make all that we need of this molecule. It is a fatty acid called docosahexaenoic acid.

Fear not if its name looks incomprehensible, it is a name invented by organic chemists to state unambiguously what the molecule is and how it is built atomically.  The name is often shortened to DHA, which I think you will agree is more manageable.  It is given the trivial name cevronic acid. Whatever we choose to call it, there is evidence that without it, several of our bodily systems would suffer.  Its presence in the nervous system is well documented [1].  The amount of DHA in a neurone’s membrane influences the action of proteins that control whether potassium, sodium and calcium ions are inside or outside of a cell.  These are proteins are known as ion channels, and although what they do might sound a bit trivial, their behaviour is particularly important for all nerves. The impulses involved in walking, talking and touching, all rely upon ion channels in order to get from or to the brain, along sensory or motor nerves.  And this is just DHA in its ordinary form, as shown in Figure 1.  DHA is also found in our eyes, in the retina in fact, and helps us to see things properly: it helps turn the light that falls on our eyes into the nerve impulses that go to the brain. So the fact that you are reading this is thanks, in part, to DHA.


Figure 1. Docosahexaenoic acid (DHA), also known as cevronic acid.

 

DHA also has a measurable effect on the lipids it is used to make. The best published example to date is also concerned with vision. DHA can be used to make phosphatidylcholine [2], whose name is also shortened, this time to PC. It is found in the membranes of cells in the eye and its job is a physical one. The PC that contains DHA makes the membranes more ‘fluid’. This is the opposite of the effect of the presence of cholesterol [link], that stiffens the membranes. The simple advantage of a more fluid membrane is that the proteins in it, such as ion channels, do not get squashed. Biophysicists describe this in terms of membrane pressure, and it is pretty easy to understand.  Imagine you are holding hands with the love of your life. It is nice to know that s/he is there, but if the grip is too little, it is not really happening, and if it is too much, it hurts.  This is rather true with a membrane: if it is too fluid, the membrane cannot resist changes in the environment and is open to the risk of falling apart.  If the membrane is too stiff, the proteins are under pressure and cannot work properly. DHA is one of the molecules that contributes to this balance.  In terms of your vision, it allows the plasma membrane of the cells at the back of your eye to be fluid enough for the proteins, called rhodopsins, to do their stuff. 

But humans have a problem; we cannot make this fatty acid.  It is nothing to panic about as we can get much of what we need from easily available sources – fresh fish being the richest natural one.  An even better one in terms of mass, is popping a cod liver oil tablet, packets of which can be bought from just about every vaguely food shop or pharmacy in the country.  The larger supermarkets have their own brands of it; it is not a difficult product to put together and sell.  In the shops it is often placed alongside vitamin and mineral supplements.  However, as it is a dietary supplement it is subject to much of the same sort of scientific and media attention as vitamin pills.  Recent evidence indicates that too much of certain vitamin and mineral goodies in our diet, can be counter-productive.  So, if you find your joints are less flexible than they once were, or your eyesight is worsening, DHA might give you a bit of a hand. However, unlike vitamin and mineral supplements, it will not shorten your life just like that.  As you are consuming a fatty acid, if you eat too much, you will put on weight instead.

References

[1] N. Salem, B. Litman, H. Y. Kim K. Gawrisch, Lipids, , 36, 945-959. http://www.springerlink.com/content/r2326m7553u64258/.
[2] B. J. Litman, S. L. Niu, A. Polozova, D. C. Mitchell, Journal of Molecular Neuroscience, 2001, 16, 237-242. http://web.pdx.edu/~drakem/papers/J_mol_neuro-2001.pdf

 

 What Do Membranes Do? Thursday, Nov 24 2011 


We know that membranes in cells are complicated, and we have a pretty good idea of what they look like (Figure 1). We also know that the plasma membrane, the membrane that is the edge of the cell, is the thing that makes the cell a cell. At the very least, it means the cell is a discrete entity, and not just a loose collection of cell parts in one place. This might seem a serious job on its own, and it is, but there is more.


Figure 1. Schematic representation of a cell’s plasma membrane, showing the lipids along with peripheral and integral proteins, glycoproteins, surface proteins, ion channels, and carbohydrates. Note also the cytoskeleton filaments that, together with the plasma membrane of the cell, give it a life-supporting structure. Picture courtesy of WikimediaCommons.

Figure 2. Schematic representation of vesicles, with lipids forming a bilayer around a small body of water with other solutes (green blobs). Picture courtesy of WikimediaCommons.

Bilayers, such as that shown in Figure 1 contain various types of protein and some bits of carbohydrate*. However, to do the job of separating the cell’s insides from its environment, none of these other components are necessary. It is perfectly possible to create a sturdy bilayer from lipids alone. When this bilayer is formed in flat sheets and stacked up four-by-two, it is known as a lamellar phase [1], and when a bilayer is shaped like a ‘bubble’, it is known as a vesicle (Figure 2) [2].  Vesicles may sound a curiosity, but they are very useful in research laboratories. They provide a sort of stepping-stone to understanding complete cells as they can be of a similar size, but are much less complicated biochemically. So, if a scientist wants to test an idea or hypothesis without the complications of a testing it on a whole cell, a vesicular system is a useful one to try it on first. If the job of being a skin, a border between the inside of the cell and the outside, can be done so simply by a lipid bilayer, why does the cell go to the trouble of having the rest of the gubbins there?

The question becomes more pressing when we consider that there are a variety of proteins in the membranes of cells of both animals and plants. Not only that but, proteins are oten more complicated to make than lipids. The question has been raised not only about cells, but also about the parts of a cell that have a membrane or mono-layer covering of lipids. These parts of a cell are known as organelles.

Murphy and Cummins [3] asked this question directly about the organelles that store oil in seeds like Brassica Napa (rape seed). It is an interesting question, and there is an understood answer.   Consider this: if you were to put together an organisation of people in order to produce, say, a new range of chocolates, you would undoubtedly want several types of person. You would want people who could physically make the chocolate itself, so that you had chocolate to sell; you would want people who could design the chocolates, so the product had a chance of being consistent, coherent and tasting good; you would want managers to over-see the work of both of these teams; you would want market analysts, a legal team, HR and so on. Many types of people, probably too tedious to name individually. But you would need something else, too. You would want them to be able to talk to one another. You, as the philanthropist of your very own chocolate–making enterprise, would need them to communicate so the company’s activity is co-ordinated and coherent. With cells, it is just the same: the various organelles need to be able to communicate with one another in order that the cell can stay alive.   In order for a cell to stay alive, it must do a multitude of things – take in food, get rid of waste, resist changes in the environment, grow and replicate, to name but a few. And of course all of this must be co-ordinated so the cell does not die. An important part of this is cellular signalling.

As you might imagine, in order to perform a complicated set of processes, cellular signalling takes on a variety of forms – just like the large vocabulary required for a whole company to communicate with itself effectively. The complexity of cellular signalling has been made clear in recent decades, and now there are at least four scientific journals that focus on this aspect of biology alone, namely Cellular Signalling, the Journal of Cell Communication and Signalling, the Journal of Molecular Signalling, and Cell Signalling Biology.   The role of lipids in cellular signalling is a wide topic, and will be examined in other entries in this blog. Examples include how insulin lowers blood sugar level, and how the cytoskeleton (Figure 1), and thus the shape of the cell, is managed.

 

References and Notes

*Anything with the prefix ‘glyco-’ either is a carbohydrate or has one attached to it.

[1] F. D. Gunstone, John L. Harwood, Fred B. Padley, The Lipid Handbook, 2nd Ed, 1994, ISBN-13: 978-0412433207.

[2] J. C. Stachowiak, D. L. Richmond, T. H. Li, F. Brochard-Wyart, D. A. Fletcher, Lab on a Chip, 2009, 9, 2003–2009.

[3] D. J. Murphy, I. Cummins, Phytochemistry, 1989, 28, 2063-2069. http://www.sciencedirect.com/science/article/pii/S0031942200979214

 

 Cholesterol: A Two-Faced Dark Horse? Saturday, Nov 19 2011 

Cholesterol causes death.  At least that is what some people seem to suggest.  Or at least if you are a man, apparently it will.  There are other examples where it seems to be implicated rather clearly in an alarming context.  However, it is equally touted as being instrumental in amazing cures.  This rather up-and-down feel to the tabloid portrayal of cholesterol is somewhat at odds with the careful marketing of certain pseudo-dairy products that are “proven to reduce cholesterol”.  This latter phrase and related ones imply, of course, that cholesterol is a bad thing.  

 It is well known that we can have too much of a good thing, especially in our diet.  Cholesterol does not quite fall into this category as just about every cell in our body can make all the cholesterol it needs [1].  As it is not a waste product, this suggests to me that it is not overtly harmful: it is obviously important that our bodies have it, otherwise they would not make it. So why is it there?  There is a lot of physical evidence that suggests that cholesterol makes up as much as a quarter of the mass of the plasma membranes of several types of human cell [2].  For other cell types, it is less, and for E. Coli bacteria, it is none at all [2].  This presence in cells is partly due to what can be made from cholesterol.  It can be made into vitamin D, known as calcipherol (usually written calciferol), a process that famously uses sunlight.  It is also the starting material for the body’s production of steroid hormones, the better-known ones being testosterone and the oestrogens.  I think these points sound like strong enough reasons for cholesterol to be sloshing around inside us, but there is more. 

Figure 1.  From left, structures of cholesterol, testosterone, progesterone and oestradiol. The latter is one of the three hormones that make up the group of oestrogens.

The utility of cholesterol is not confined to vitamins, sex and puberty.  The structure of cholesterol (Figure 1) shows very little functionality that can interact with water, suggesting that it is more lipophilic than hydrophilic.  If it cannot dissolve in water, thermodynamic favourability would suggest it is found in fattier parts of the cell.  This is indeed the case, with as much as a quarter of the plasma membrane’s mass being cholesterol, it seems reasonable that it must have a physical impact on the properties of the membrane, implying that it must have some purpose.  This has indeed been researched, and the results suggest that the presence of cholesterol stiffens the membranes [3].  This is described as a change in the membrane’s fluidity [4], with higher cholesterol giving rise to greater stiffness.  Thus cholesterol is part of the system that gives a cell its shape.  If you are thinking that most cells are rather shapeless blobs, consider for a moment how different the shape of a sperm cell is to a red blood cell, or an ovum.  For some, their shape is very precisely controlled.  

The stiffening of the plasma membrane has further ramifications for diffusion across the membrane.  Sodium ions, potassium ions and water diffuse more easily across more fluid membranes.  Thus the presence of cholesterol influences the speed of diffusion of these particles.  These are important things that the cell must keep a check on in order to survive. It is perhaps particularly surprising to note that cholesterol is able to achieve all of these things without being a lipid – it is not amphiphilic.  However as it is so closely associated with lipids and lipid systems, it is usually given a place in databases on the subject, as well as in journals on the physical chemistry of lipids.  

The fact that cholesterol has its fingers in many bodily pies does rather beg the question of what happens when cholesterol is too high.  Physically of course, we can imagine that the membrane will be stiffer than is optimum, reducing the cell’s ability to change shape without being damaged, and with compromised diffusion across the membrane.  But what else?  The easy answer is what is known as furring of the arteries, so called due to the appearance of the inside wall of the arteries under such circumstances.  In reality, no fur has formed.  What has happened is in fact physical and is related to the hydrophobic effect.  Cholesterol, not being able to dissolve in water, concentrates here along with calcium salts.  The latter is a well understood and unrelated phenomenon that is age-related.  The suggestion arising from concentration of cholesterol in arteries is, naturally, that too high a level of cholesterol means that there is more to deposit.  

This gives a rather nasty sting in the tail for a molecule that is otherwise rather essential for us to be what we are; in fact no vertebrate would be able to reach adulthood without its derivatives.  What this story serves to highlight is the double-edged nature of many of the lipid-related biological molecules: not only can we have too much of a good thing, but too much of an essential one as well.

References

[1] F. Xu, S. D. Rychnovsky, J. D. Belani, H. H. Hobbs, J. C. Cohen, and R. B. Rawson, Proc. Natl. Acad. Sci. USA 2005, 102, 14551-14556.  http://www.pnas.org/content/102/41/14551.full

[2] P. L. Yeagle, Biochim. et Biophys. Acta, 1985, 822, 267-287.  http://www.sciencedirect.com/science/article/pii/0304415785900115

[3] K. E. Bloch CRC Crit. Rev. Biochem., 1983, 14,47-92.  http://informahealthcare.com/doi/pdfplus/10.3109/10409238309102790

[4] J. A. Clarke, A. J. Heron, J. M. Seddon, R. V. Law Biophys. J., 2006, 90, 2383-2393.  http://www.sciencedirect.com/science/article/pii/S0006349506724213

 

 “Bubbles, Bubbles, Everywhere, But Not a Drop to Drink” Friday, Nov 11 2011 


Soap is something we all use every day, without even really thinking about it.  Well, most of us use it every day.  But how much do you think about it?  Do you feel you know what it does or how it works?  Do you even need to know either of these things?

Of course it is perfectly possible to live a full and active life without knowing anything about soap at all.  Most people get as far as which one(s) they like the smell of, and possibly which ones their skin does and does not react well to.  What might help with the latter, as well as the behind-the-label study of these products, would be some understanding of the terminology used on these toiletries.  For example, Pears® now market something for washing hands that is “100% Soap-free”.  Bayliss and Harding market a “cleansing hand wash”, that is not soap free. 

In order to understand the difference between these two, and believe me they both wash your hands perfectly well, we need to know what soap is, and what it does. It may seem trivial, but I would also suggest we need to know what its purpose is as well, so the stuff we rub all over ourselves in the bath does what we want it to.

Figure 1. A cross-section of a micelle of the type formed by surfactants. The orange region (middle) is the grease around which the surfactant molecules are packed. Photo copyright: www.flatworldknowledge.com.

The obvious job for soap is to clean us, our clothes, our house/office etc., one way or another.  What it is doing of course is removing grease and dirt.  It does this by making the grease and dirt soluble in water.  If you are thinking either that something like a lipid could perform this task, or, that such a mixture of grease and water is an emulsion, you are absolutely right.  Tragically, although lipids are good at dissolving grease, they are often hard to wash away completely with just water.  So we need something slightly different for this job.  We need something that is more like a surfactant. As it happens surfactants and lipids are quite similar.  They both have sections that like water (hydrophilic), and sections that like grease (lipophilic).  However, the self-assembly properties of surfactants are slightly different to those of lipids. Typically, lipids form bilayers or cylinders, where surfactants form micelles (Figure 1).  Micelles are particularly good at trapping grease as the surfactant molecules can fit around the grease droplets, with their water-liking head groups facing out. This allows the grease to dissolve in the water and therefore be washed away.
 So we know what these sorts of molecules are doing physically. But what is soap?  Well, like lipids and surfactants, in order to dissolve grease into water and form an emulsion, it needs aspects of both water and grease to be an effective emulsifier. Soap is in fact made from fat, known to scientists as fatty acids. The fat is boiled up with some caustic soda (sodium hydroxide), and so we have made a sodium salt from the fatty acid (Figure 2). This is more or less how soap has been made at least as far back as Tudor England. The source of fat in that case was mutton, and the hydroxide was cobbled together from heating mens’ urine. These days, sodium hydroxide is commercially available, and a variety of sources of the fat are used – everything from whale blubber to olive oil.

Figure 2. The preparation of soap from a fatty acid, using sodium hydroxide. This is essentially the same chemical process that has been used to make soap since Tudor times, and is also how it is apparently made in the film Fight Club. In the film, the main character uses fat from liposuction patients to make cakes of soap that he then sells to reputable shops.
 
 
 
So that is not only the physics but chemistry of soap covered. One last thing you may like to know: how can we have soap-less soap? Well, ‘hand wash’. Lateral thinking would suggest that we need a surfactant that is not made from a fatty acid. And that is more-or-less what we use. The most common one is usually called sodium lauryl sulphate on packaging, though there are a couple of different names that are similar to that one. It is commonly used in shampoo. Scientists call it sodium dodecyl sulphate and it has many uses. For example, is used by molecular biologists to separate proteins according to their size. Think of that next time you are washing your hair.  

 

 

 The Structure of a Membrane Saturday, Nov 5 2011 


Every cell has a membrane.  The membrane is often described in simple terms as being like the ‘skin’ of a cell.  Without the membrane, the cell would die, in a similar way that if a person lost their skin, they would die.  However, this does not tell us much about what the membrane is or how it is constructed.  

We know from the structure of lipids that they are amphiphilic.  This means that part of the lipid likes greasy substances and part of it likes water.  This bi-polar structure is at the heart of the behaviour of lipids and can be observed when they are exposed to water.  When lipids are put into water, the lipid molecules re-arrange so that the water-liking section faces the water, and the greasy-section is shielded from the water (known as self-assembly).  This is behaviour is driven by the hydrophobic effect.  The hydrophobic effect is an important one in the construction of biological membranes.  The presence of water means that the lipids assemble themselves into a bi-layer.  This bi-layer* contains two ‘sheets’ of lipids (called mono-layers) in which the head groups (water-liking sections) face towards the water, and the greasy sections (tail regions) face away from the water and towards one another, Figure 1.   This satisfies the hydrophobic effect because the greasy sections are shielded from the water, where the water-liking sections are allowed to interact with it.  Biophysicists describe this in terms of energy: it is energetically favourable for the water-liking parts of the molecule to interact with the water, and energetically favourable for the greasy parts not to interact.  


Figure 1. Left: The assembly of lipids when exposed to water (marbled blue region). The plain blue areas are the water-liking regions of the lipid molecules (head groups), with the red sections showing the greasy sections (tail groups). Right: These regions are shown in an example lipid, phosphatidylcholine. Figure 2) and was proposed in the journal Science in 1972 [1].  This model is based on the idea that the membrane is flexible and molecules can move sideways in the mono-layers, allowing different parts of the membrane to do different things.  

Figure 2. Fluid Mosaic Model proposed by Singer and Nicholson. Diagram from Alberts et al. [2].

However, recent evidence suggests that the Fluid Mosaic Model is a bit simplistic.  Certain important processes in a cell’s life cycle are not well explained by it.  This includes cell division, in which the membrane must also be divided.  There is also evidence that the cell’s internal signalling processes use the membrane.  Another aspect that must be taken account of is that the membrane does not exist independently of the rest of the cell. It does not just sit there.  The membrane is shaped by something called the cyto-skeleton. This is a network of tubes made of protein that appears in all types of cell, and like our own skeletons is far from inert and unchanging.    

So, the poor old Fluid Mosaic Model has been superseded. Even it was not fluid enough to keep up with newer understanding.  Although the more recent research has allowed us to see how crucial the membrane is in the running of the cell, it left biologists with a problem.  How do we advance our knowledge of the membrane?  Several approaches have been taken.  One of these is to look at the physical behaviour of membrane constituents to find out what their contribution to the system is. This data is then used to build up a picture of the relationships between the different molecular components.  This approach is called reductionism and is related to the method used by Leland Hartwell, Tim Hunt and Paul Nurse and others in discovering the role of certain proteins in the control of the cell cycle.  It has been used to inform our understanding of the physical role of structural proteins (e.g., the BAR domain [3]) as well as lipids such as phosphatidylinositol [4], and cholesterol [5].    

The evidence that a reductionist’s approach has started to bear fruit is that ‘synthetic cells’ [6] have been made.  The fact that it is possible to prepare such entities, albeit basic ones compared with many if not all cells in nature, suggests that the accumulating understanding of the components of cells is broadly representative of the systems found in nature.   

References

*this word is frequently unhyphenated.

[1] S. J. Singer, G. L. Nicholson, The Fluid Mosaic Model of the Structure of Cell Membranes, Science, 1972, 175, 720-731.  http://www.sciencemag.org/content/175/4023/720.abstract?sid=5f637971-587b-43b6-b304-14a62e7f9114.

[2] B. Alberts, D. Bray, J. Lewis, M. Raff, K. Roberts, J. D. Watson. Molecular Biology of the Cell; 3rd ed., Freeman, 1994.

[3] W. M. Henne, H. M. Kent, M. G. J. Ford, B. G. Hegde, O. Daumke, P. J. G. Butler, R. Mittal, R. Langen, P. R. Evans, H. T. McMahon, Structure, 2007, 15, 839-852. See also Pykäläinen et al. Nature Structural & Molecular Biology, 2011, 18, 902–907, and Dawson et al., Trends in Cell Biology, 2006, 16, 493-498.

[4] X. Mulet, R. H. Templer, R. Woscholski and O. Ces, Langmuir, 2008, 24, 8443–8447. http://pubs.acs.org/doi/full/10.1021/la801114n.

[5] D. A. Brown, E. London, The Journal of Biological Chemistry, 2000, 275, 17221-17224. http://www.jbc.org/content/275/23/17221.full.

[6] T. F. Zhu, J. W. Szostak, Journal of the American Chemical Society, 2009, 131, 5705-5713. http://pubs.acs.org/doi/full/10.1021/ja900919c.

 

 Ransom™ Pure Lecithin – Product Review Wednesday, Oct 26 2011 


Figure 1. The “Pure Lecithin” produced by Ransom™ Image © Samuel Furse MMXI

It is not very often that something is so clearly adrift that I think it needs critical analysis.  This, however, is one of those times.  “Pure Lecithin Granules” produced by Ransom™ is a very innocent-looking product (Figure 1).  So what is there that could be to discuss?  I could be about to examine Ransom™’s legal position with respect to this product, or their marketing, or their science.  The label is green and yellow, and it has pictures of clean-looking vegetable matter on it (see photograph Figure 1).  So they probably have their marketing fairly well nailed.  I am not trained in law at all, and so that aspect I leave alone at present.  That leaves us with the science. The first thing that caught my eye was the phrase “Pure Lecithin”.  In lipid chemistry (and membrane biophysics) the term ‘lecithin’ means phosphatidylcholine.  This is bourne out by the products available from reputable suppliers such as this one and this one.  ‘Lecithin’ is an informal word and so there is some flexibility over its meaning, but this only extends to the detail of the fatty acid residues  (Figure 2).  This is where the use of the word ‘pure’ by Ransom™ meets its first serious slippery patch.  Lecithin is by definition a mix of phosphatidylcholine molecules, thus a concept of ‘pure’, seems at best imprecise.  Further, the very detailed nutritional information on the packet shows that there are at least four molecules present that are not phosphatidylcholine (‘real’ lecithin).  Three of these are the lipids phosphatidylinositol, phosphatidylethanolamine and phosphatidic acid.  The fourth is listed as “carbohydrate”, and is presumably yet another mixture.  Thus ‘purity’ with respect to this product is therefore debatable. The second phrase that leaps out with crashing force is “helps in the breakdown of fat”.  That suggests to me, as a consumer, that this stuff will not only help your body deal with fat in a way that is harmless to you but also basically reduce the amount of fat you will gain from the food you eat.  This phrase is therefore a good piece of marketing — it sounds good, but means almost nothing. What is true is that this collection of lipids (with a bit of carbohydrate), will help to dissolve fatty materials in water and form an emulsion of the fat and the water.  The “Lecithin” is therefore an emulsifying agent.

Figure 2. Phosphatidylcholine (Lecithin). The red section represents the hydrophilic (water-loving) section, where the blue represents the greasy-loving section. The latter is typically a mixture of types in lecithin.

It is perhaps not surprising that it has a molecular structure that is chemically sympathetic to both water and fat.  It is well known that water and fat do not mix.  That lipids allow this to occur makes them the metrosexuals of chemistry in that sense.  However, the fact that there are similarities between lipids and fats might ring alarm bells for you.  And you would be right.  As it happens, the molecules that make up fats, called fatty acids, form part of the molecular structure of lipid molecules.  In fact they are the weightiest part (see Figure 2).  This is why this “Pure Lecithin” is in fact 91% fat by mass.  So much for helping with the breakdown of fat, and being good for a healthy diet. 

So after deconstructing their presentation of anything even vaguely scientific, or indeed apparently healthy, do I have anything good to say about this product?  Well, sort of.  Mixtures of lipids are occasionally useful to me as a research scientist, with known components such as this it can provide a vague sort of comparison for other, unknown, lipid systems.  It provides a cheap source of such a mix of known lipids and so ideas about lipid experiments I have in the bath or at other inopportune times can be tested without spending much money.  But would I use it in food?  Certainly not.  It smells of nasty paper glue in my opinion and gets awkwardly sticky if it goes near water, even if we ignore the above shortcomings.  It may seem unkind, as they clearly go to some trouble to produce a food-grade product, however when something appears ill-presented on close inspection, could I really trust it?  Fat chance.

 

 

 What is a Lipid? Tuesday, Oct 25 2011 

For most people who have heard it, the word lipid sounds like the scientific word for fat. Although scientists tend not to use the word fat, and do tend to use the word lipid, the two do not quite match-up. When we say fat in the context of food, we think of cooking or olive oil, butter, grease and possibly cream. Perhaps confusingly, all of these have lipids in them, but none of them are pure lipids.

The confusion about these strange molecules is probably related to the fact that they are hard to pin down. There is virtually an art form in isolating them. Only in the last 50 years have we really started to understand them, or their role in biology. The thing that makes lipids what they are, is that they are what is known as amphiphilic. This is from the Greek ‘amphi-‘, meaning ‘both’, and ‘‑philic’, meaning ‘loving’. Although this sounds like an intellectual’s way of referring to a bisexual person, here the ‘both’ refers to water and grease. As we know, water and grease do not mix: if we pour oil onto water, the two just sit there. Lipids are special because they can dissolve in both of them. This property can even be used as a way of mixing grease and water together. Homogenous mixtures of grease and water with another agent are known as emulsions. Examples include milk, cake batter and margarine. The emulsion as a construct is useful in the manufacture of foods, giving rise to a plethora of agents that are able to perform this role, namely emulsifiers. Although in theory all lipids can be emulsifiers, not emulsifiers all are lipids.

We can see the roots of the amphiphilic behaviour in the structure of the lipid molecules. Moreover, structural analysis of molecules can help us determine whether or not a molecule is a lipid at all, and if so, which sort. Figure 1 shows an ordinary lipid with the head (water-loving) and tail (grease-loving) regions marked out.

Figure 1.  Phosphatidylcholine (Lecithin). The red section represents the hydrophilic (water-loving) section, whereas the blue represents the greasy-loving section.

The structural approach has been used by several institutions in recent years, including Lipid Maps.  This has given rise to a broader definition of the term lipid.  Thus, a variety of compounds not traditionally referred to as lipids are included, even if they are not measurably amphiphilic. However, when these ‘sort-of lipids’ are inserted into lipid systems whose physical behaviour is well understood, their influence on the character of the system is measurable.  This influence of the added component is also described as concentration-dependent, i.e., the more of the molecule that is put in (the higher the concentration), the stronger the given effect.
Some of the most amazing and unexpected behaviour of lipids occurs when they are exposed to water.  As part of the molecule likes water, and part of it does not, you can imagine that this situation is not going to be simple for the poor little lipid.  We as scientists describe the stresses and strains in systems like these according to the laws of thermodynamics.  Those of a certain generation may like to remind themselves of the Flanders and Swann song at this point.  Either way, we have put an unsuspecting lipid into a system with water and so what does it do?  Generally, lipids will self-assemble.  The exact manner in which this occurs varies between types of lipid, but the principle is observable across all of them.

The principle of self-assembly can be explained in terms of two competing priorities.  Thermodynamics means that the grease-loving (lipophilic) part of the lipid molecule wants to be shielded from the water, but at the same time, the water-loving (hydrophilic) part wants to be in touch with the water.  As our lipid cannot bear to disobey the laws of thermodynamics (who would?), it arranges itself in order to compromise between these competing forces.  This compromise can also be described in terms of energy.  In order to adopt a position in which the greasy section is exposed to water requires a lot of energy.  When the energy that is available to the system is insufficient for this, exposing the greasy section of the lipid to the water is described as energetically unfavourable.  This is the thermodynamic law I refer to and is also known as the hydrophobic effect.  The latter term, as you might well guess, is from the Greek ‘hydro-‘ meaning ‘water’ and ‘‑phobic’ meaning ‘hating’.

The hydrophobic effect may sound obscure, but the forces involved in it are what hold the membranes of cells together.  This means it has a huge and unsung part to play in understanding biology.

 

 

 Introduction Tuesday, Oct 25 2011 

Lipids are not sexy.  They do not give anyone erotic stirrings, they do not start revolutions or catch criminals.  However, without them, life as we know it would simply not exist.  Let me explain.

Cells are well known as the smallest units of life.  Their discovery in London in the 17th century by Robert Hooke raised, and continues to raise, a bewildering array of questions:  ‘What makes them alive?’ ‘What molecules are cells made of?’

We now understand that there are only about three types of large molecule that make up the physical blocks of life.  Nobel Prizes have been won for work on two of these, namely, DNA [1] and proteins [2].  The understanding that work on DNA and proteins has given us has led to other questions.  For example, not only has the structure of DNA been discovered but its’ purpose is now also understood.

The link between these first two classes of molecule is that the DNA codes for the proteins.  DNA is divided up into genes, and one gene codes for one protein.  Proteins are the machinery that allow cells to work.  With proteins, cells can exert control on the chemical processes that are essential to survival.  But what about the bits in-between the proteins in a cell?  What about the bricks and mortar that hold the cell together?  It is a good question.  This is the job of the third class of large molecule that makes cells what they are: lipids.

Windows, doors, tables, chairs, bookcases and novelty vacuum cleaners all tell you a lot about a house.  But, like the proteins of a cell, they need something to hold them together in order to make them a house and not just the contents of a skip.  In building a cell, that job falls to lipids and therefore the analogy with the brick is not as distant as it might sound, either metaphorically or practically.

Lipids come as many varieties, though they are rarely unique.  Individual parts are never a focus when looking at the whole construct, but of course we notice when they are not there.  And when they are there they do not seem to do much.  But they have a physical job: crudely, they fill up the space in between the more interesting bits and hold them in place.  This is perhaps why they have not received as much scientific or media attention as other components of the cell.  This is why they are not ‘sexy’.  In any case, they are better than that.  They are useful.

References

[1] F. H. C. Crick, J. D. Watson, M. H. F. Wilkins, Nobel Prize for Physiology, 1962.  http://www.nobelprize.org/nobel_prizes/medicine/laureates/1962/

[2] L. H. Hartwell, T. Hunt, P. M. Nurse, Nobel Prize for Physiology, 2001.
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/

 

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