The concept of nutritional phenotyping

A little bit of Greek never hurt anybody so lets first look at the term ‘omics’. It is widely used in scientific literature to refer to the new sciences of genomics, which is derived from the term ‘genome’. According to Wikipedia, the term (‘Genom’), coined by a German scientist Professor Hans Winkler of the University of Hamburg in 1920, is from the Greek word ‘I become’. The term ‘ome’ is also of Greek origin and means ‘totality’. From the term genome, came the term genomics, the study of the genome. We then entered the freewheel of ‘omics’ where the study, not just of one protein, but of all proteins measurable within a biological sample, became proteomics. Not to be outdone, those interested in metabolites coined the term ‘metabolomics’ to refer to the science of studying not one but hundreds of metabolites at one time, using pattern recognition technology to seek patterns within the vast amount of data generated. There the matter rested although a proposal for the entry of a new term ‘astrobolomics’ was mooted at a significant scientific meeting on Copenhagen just a few years back. The thinking behind this was that all of these omics could no more predict the future that astrology and that it was all a load of b******.  Hence the proposal for astrobolomics.

All of these omics were eradicating traditional whole body physiology in what can only be described as a technology driven reductionist biomedical Klondike. They had wonderful terms such as ‘knock out’ and ‘knock in’, ‘upstream’ and ‘downstream’, ‘introns’ and exons’ and others, which I always thought would be excellent as the lyrics of some, rap song. Not only were all the omics the only show in town, but when they were blended together they ascended into a new level of mind blowing stratospheric science called ‘systems biology’, in which their blend, through great number-crunching  brontobyte computers (a 1 followed by 27 zeros....forget a google) would lead us to biological Nirvana. This was the future, the autobahn of the new biology.

But as the song goes, with minor adaptations: “And then they went and spoiled it all by saying something stupid like phenomics”. This very new term refers to the very, very old term ‘phenotype’ which comes from the Greek words phainen (‘to show’) and typos (“type”). It really means the study of what you are like: height, weight, eye colour, IQ, fitness, blood this and blood that and just about everything measurable in the human body. To study phenotype is really to study form and not function. The emergence of phenomics is not actually a surrender note from the reductionist hoards on the omics autobahn, just a realization that when you add up all your biology, you ultimately end up with a phenotype. Some of us, blessed with a traditional reverence of the totality of human biology, nutritionists in particular, saw the need for this a long time ago. One could ay that the concept of the nutritional phenotype was born about ten years ago and several people need to be mentioned here for promoting this concept: Ben van Ommen of TNO, head of the European Nutrigenomics Organisation

, Jim Kaput who headed up the FDA’s Division of Personalised Nutrition (now with the Nestle Health Institute) and if I do say so myself, mé féin (copy, paste and Google translate).

In Ireland, a consortium of four universities (Joint Irish Nutrigenomics Organisation: JINGO) received state funding to create a National Nutritional Phenotype Database

. It contains data on several cohorts which have had their phenotype characterised to a remarkable extent (food intake, physical activity, bone density, body fatness, energy expenditure at rest and at exercise, blood this and blood that, muscle function, post prandial function and so on.  In addition we payed homage to the gods of omics and collected complementary data on genomics, proteomics and metabolomics. The difference between this approach and that of systems biology is that we begin with phenotype in either the healthy state or the diseased state and we work back from there. Generally speaking, systems biology builds upwards from genomics, proteomics and metabolomics data to try to understand the mechanisms that lead to disease. Of course it isn’t a competition between systems biology and the construction of major phenotyping databases but the subtle difference is that the latter is driven by phenotype, the former less so and maybe more so now that they have discovered ‘phenomics’.

Such large phenotypic databases need to have several cohorts, central to which should be a large, healthy, nationally representative cohort. This database will always act as the reference database. If you want to know anything about the nutritional phenotype of the Irish, then we have 1,500 such subjects deeply characterised for their phenotype and of course their ‘omics’. Then you need at least one database, which involves a challenge to metabolism. We have two such. One involves a small number (210) who received test meals on two separate occasions and had their metabolic phenotype characterised after either a carbohydrate or fat meal. Almost everybody knows that when you have to attend for a blood test, you usually have to fast from the night before. If everyone were to arrive in at different times, having eaten very different breakfasts, then the interpretation of the blood tests would be confounded by this variation in food intake. So, virtually all the scientific data we have relating diet to health has blood samples measured in the fasting state. This is convenient for the clinician and researcher but it avoids the truth, which is that we eat about 5-7 times a day, and thus we spend most of our day in the postprandial or post-fed state. So, a knowledge of how dietary patterns relate to blood values at fasting is simply a measure of convenience, a means of reducing what is truly complex to a simple and manageable form. Metabolism is asleep in the fasting state and only comes alive in the fed state. Two individuals with identical levels of say fasting blood glucose may behave very differently when given a carbohydrate rich test meal. These test meals really sort out the chaff from the straw in metabolic terms. The second stressed cohort that we have is a very large cohort of older persons: 2,000 with bone disease, 2,000 with impaired cognitive function and 2,000 with high blood pressure.

We have spent the last 5 years building this database, which I equate to the building of a telescope. Now that it is almost finished, we will be equipped to peer deeper into the interaction of diet, genes and metabolism than many others can. 

Shading the sunshine vitamin

Just a few weeks ago, the nutrition community in Ireland gathered in the small town of Limavady in Northern Ireland to lay to rest one of ours, the late Dr Julie Wallace, an outstanding academic at the University of Ulster. Julie was young and in the prime of her scientific career which centered around vitamin D, the topic of this week’s blog and I will draw on a very recent paper of Julie’s in outlining what vitamin D does and doesn’t do. The main function of vitamin D is to facilitate the absorption of calcium from the gut, and then to facilitate its transport from blood into bone cells where it is used in bone growth. The earliest indication of vitamin D deficiency is rickets in children where their normal bone growth is impaired due to inadequate calcium levels, directly arising from poor vitamin D status. When expert committees sit down every so often to pour over the scientific literature to come up with dietary recommendations that ultimately find their way to your packet of Cornflakes, they usually leave vitamin D to the last. That’s because vitamin D is the “sunshine” vitamin. Every cell in the human body makes cholesterol for its own needs and one of the building blocks of cholesterol is acted on by UV light in skin cells leading ultimately to blood vitamin D. In effect, the impact of sunshine on the body’s vitamin D status was generally held by these committees to far outweigh dietary sources, thus downgrading its nutritional importance.

Then, out of nowhere, vitamin D began to climb up the popularity ratings in human nutrition. Firstly, the bizarre finding of inadequate blood levels of vitamin D in sun drenched Australia, began to raise concerns among nutritionists that over-zealous protection from sunrays to reduce the risk of skin cancer might in fact have an unexpected adverse effect. The Aussies developed a major communications programme around “Slip, Slop, Slap” (slip on long sleeved clothing, slop on sunscreen and slap on a hat). Australia has the highest level of skin cancer in the world and their cancer authorities recommend that fair skinned people can get enough vitamin D in summer from a few minutes of sunlight on their face, arms and hands before 10 am or after 3 pm on most days of the week.

This downgrading of vitamin D by the cancer specialists, began to conflict with new findings of a potential role of vitamin D in heart disease.  A significant body of data had begun to emerge ten or more years ago, linking low vitamin D status to the adverse effects of obesity, specifically the “metabolic syndrome” (insulin resistance, impaired glucose function, high blood lipid level and high blood pressure). The vast majority of these studies were “observational” meaning that in an available cohort, people with the metabolic syndrome had generally speaking lower levels of blood vitamin D. Of course, this cannot prove cause and effect. For example, people with the metabolic syndrome are overweight or obese and it could be that obesity was causing the low vitamin D levels and not the other way round. Indeed, that is exactly what a very recent paper from the late Julie Wallace shows and of course it makes intuitive sense

. Vitamin D is a fat-soluble so it prefers a fatty environment than a watery one. Thus the more fat we lay down, the more vitamin D wants to move from blood, which is a watery tissue to fatty tissue. In effect, fat people dilute their blood vitamin D levels raising the question as to whether the overweight and obese need higher than average vitamin D recommendations.

Thus the putative link between vitamin D and the metabolic syndrome and obesity is not looking so good. The only real test comes from an intervention study and myself and my colleagues here in UCD led such a study along with our collaborators in UCC. We gave 160 subjects either a reasonable dose of vitamin D (shown in previous studies to raise blood vitamin D levels within 4 weeks) or a placebo over a 4 week period and we completed this study in two phases: in the sprong just after te darkest part of the year and in Autumn, just after the sunniest part. Vitamin D levels rose in the group given vitamin D but there was no effect on any one of the 14 blood markers of the metabolic syndrome that we measured.  We then decided to rank the subjects into those with very low and very high initial levels of blood vitamin D to see if we could find an effect at the extremes. We didn’t. We then moved into new territory for this type of research using a statistical technique known a cluster analysis. Effectively, you say to the computer (You know that I know that you don’t actually speak to computers so get metaphoric please) to sort the subjects out into groups according to our 14 blood markers of the metabolic syndrome such that subjects within a cluster share a common profile and the different clusters are quite different from one another. We then asked if any one of these clusters responded to vitamin D therapy and one did. It was characterised by low levels of vitamin D in blood AND high levels of two special hormones released into blood from adipose tissue (resistin and adiponectin).

So our data would suggest that there is a subset of the population who do show quite a dramatic reduction in the adverse effects of obesity in response to vitamin D.

This is an issue that will remain on the agenda for some time to come given the intense and opposing views on this topic. What the data does show is (a) that one well designed intervention study is worth a thousand observational studies and (b) future intervention studies will have to classify people into groups which balance not just age, weight, sex and so forth but their genetic and metabolic sensitivity to the intervention. The future just got personal.

Sugar ~ Pure, White and Misunderstood

Few of the nutrients in food attract a more negative agenda than sugar. I recall early in my career a famous or, in hindsight, an infamous book entitled “Pure, White and Deadly” written by John Yudkin, then Professor of Human Nutrition at the University of London. Not a year has gone by since then, that sugar and its attendant industry, has not been strapped to the whipping post for a thorough reminder of its evil properties. One of the most recent was a ‘Comment’ in Nature which equated sugar with alcohol as a substance of abuse and addiction meriting the guiding hand of Miss Nanny State to help us free ourselves of its dangers, through tax and other regulatory measures. In relating sugar to alcohol, the first parallel is that there is now unfettered access to a high sugar diet, which according to the authors, is a new phenomenon. They write thus: “First, consider unavoidability. Evolution­arily, sugar was available to our ancestors as fruit for only a few months a year (at har­vest time), or as honey, which was guarded by bees. But in recent years, sugar has been added to nearly all processed foods, limiting consumer choice”[1].   If I got that in an essay from an undergraduate, I would have annotated it with the letters “WTF”. (If you don’t get that, then simply Google it [2].)

The missing bit is somewhere in between “our ancestors” and “in recent years”. Honey, was one of the great luxury foods, bees or no bees, for centuries. Virgil wrote about it thus: “Next I come to the manna, the heavenly gifts of honey…one that can load me with fame”. The God Zeus was fed from childhood on honey. Sugar cane came later but well over 1,000 years ago, first recorded in T’ang dynasty (AD 766 to 790). The first known industrial sugar cane refinery was built on the Greek island of Crete in 1000 AD, the island of Crete being known as Qandi in Arabic, hence the name Candy[3] (bet you didn’t know that)!!!  So sugar didn’t suddenly appear in the last few decades.

One of the problems linking sugar with health is that the term sugar is a chemical term referring to a very specific group of chemicals called “saccharides”: “Any of a series of compounds of carbon, hydrogen, and oxygen in which the atoms of the latter two elements are in the ratio of 2:1, especially those containing the group C₆H₁₀O_5”. Glucose is the most abundant saccahride and because it is alone, single in the sugar world, it is a monosaccharide. Fructose is next and then we meet disaccharides where sugars are paired off. The most abundant pairing is glucose with fructose and that is what we know as “sugar”, in the sense of the white crystalline material in the sugar bowl. Simple? You would think so but my UK colleagues have managed to create quite a complex issue from this, fortunately not followed by many other countries. Let me explain. Here I am at my breakfast table. In front of me is a bowl of oranges, which contains one less orange that two minutes earlier, since I took one of the oranges, cut it in two and used a manual juicer to extract the juice. That juice is in a glass on my right. Now according to the UK authorities, the sugar in the orange in the bowl in front of me is an “intrinsic” sugar, a natural part of the plant. The fact that I made juice from it means I changed the sugar from being intrinsic to being “extrinsic”, that is a sugar outside its natural plant environment, which now lies in the glass to my right. The UK decision to adopt these definitions was not based on extensive epidemiology, which showed that intrinsic sugars were “good” and extrinsic sugars were “bad”. Rather, it was based on the general negative nutritional view among some (ideological rather than scientific in my analysis) that “sugars are just plain bad” and the need to square that stance with the belief that some foods, which were definitely “good”, such as fruits had sugar in them. So there had to be good sugars  (intrinsic) and bad sugars (extrinsic).

When the epidemiological evidence linking sugar intake to obesity emerged as completely inconclusive, a new concept evolved to the effect that glucose, one item of the sucrose pair, was probably ‘ok nutritionally” (they had little choice here since starch is digested and absorbed as glucose and starch was a very “good” carbohydrate) but that the other half of sucrose, namely fructose was the real culprit.  According to the Comment in Nature, sugar compares almost precisely with alcohol in its effects on humans. In a table entitled “Excessive consumption of fructose can cause many of the same health problems as alcohol” they list conditions such as high blood pressure, heart disease, impaired glucose function, obesity, pancreatitis, liver disease (fatty liver) and addiction (habituation) to chronic fructose intake. Frankly, these are extreme views based largely on (a) the extrapolation of animal studies with extreme diets to humans and (b) association studies in human nutrition epidemiology, which have not been subject to verification with dietary intervention studies. Take one example, chronic fructose intake and obesity. A major study, which reviewed all known intervention studies (n=41 studies) of the chronic effect of dietary fructose on obesity in humans, was recently published by some of the world’s most respected specialists in carbohydrate nutrition, a study fully funded by the Canadian Institutes of Health Research with zero industry funding[4]. I report their conclusion in full: “Fructose does not seem to cause weight gain when it is substituted for other carbohydrates in diets providing similar calories. Free fructose at high doses that provided excess calories modestly increased body weight, an effect that may be due to the extra calories rather than the fructose”. So this independent review of the direct effect of chronic intake of fructose on obesity finds the villain innocent. Will that placate the naysayers of sugar in human nutrition? Not at all. However, I would once again remind them of my favourite quotes to those who resolutely adhere to pet theories. Addressing the Assembled Church of Scotland, Oliver Cromwell exorted them so: “Gentlemen, in the bowels of Christ, I beseech thee, think it possible you may be wrong” or Sir Peter Medawar, Nobel Laureate in immunology who wrote in his book “Advice to a young scientist”: “The intensity with which an hypothesis is held to be true has no bearing on its validity”. And finally, from Professor Rose Frisch, the subject of last week’s blog whose work was always controversial when she was asked how did her work finally reach acceptance, she replied: “Funeral by funeral”!!

Whipping sugar is popular. It makes people feel good, it is good media friendly and it is a joy to ministers for health who would rather discuss anything bar waiting lists.  But it is rooted in atrocious science with one exception, dental caries. Sugar is to be enjoyed and if you’re watching your weight, artificially induced sweeteners are to be enjoyed. My religious friends tell me, that sugar hasn’t yet reached the sinful threshold.

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[1] Lustig, RH et al (2012) “The toxic truth about sugar”. Nature, 482, 27-28

[2] http://www.internetslang.com

[3] “History of Food” by Maguelonne Toussaint-Samat, Blackwell, Oxford

[4] John L. Sievenpiper, et al (2012) Effect of Fructose on Body Weight in Controlled Feeding Trials - A Systematic Review and Meta-analysis. Ann Intern Med. 156:291-304.

Female fat and fertility

Female fat and fertility[1]

For most females, fat is a nuisance. Like a bad guest, it arrives apparently uninvited, lingers far too long and is hard to get rid of. There is a certain level of body fat that each woman would like and it is that level of fat that makes her feel and look good. Whereas today we view female fat in terms of style and fashion, in times gone by, female fat dominated the subject of fertility. Most of the ancient symbols of fertility, such as the 30,000BC Venus of Willendorf, were of seriously fat women.  The conclusion of a successful pregnancy requires about 50,000 calories over and above normal daily living and exclusive breast feeding, the only option in times gone, by requires about 500 to 1000 additional calories every day. Unless women have some fat reserves to take this task on, bearing in mind that food might become in short supply during pregnancy, then it is not wise to travel down this reproductive road. It isn’t as though women have to make a difficult decision themselves. Nature does it for them.

The first road to fertility begins with the onset of menstruation or menarche.  In the middle of the 19^th century, the mean age for menarche was 17 years. A century later that had fallen to 14.5 years and in the US it now stands at 12.8 years[2]. These changes are due to improved nutrition resulting in young girls reaching the magic number at an earlier age. That magic number relates to body weight and the actual magic number is 46.7 kg (103 pounds). During their growing up period, children grow in a fairly linear manner (not withstanding the comments of aunts and uncle’s that “My, hasn’t she just shot up”). In today’s terms, at or around 9.5 years on average, a major growth spurt occurs in young girls. In addition to the laying down of the female reproductive tissues, there is a sudden spurt in the laying down of fat. About 2 years later, this dramatic growth spurt slows down (no one knows why) and about 6 to 8 months later, menstruation begins. Most of these data are based on detailed longitudinal studies of growth in US girls in Berkeley, Boston and Denver between 1940 and 1950. Some girls reach menarche earlier and some later, that being a feature of normal distribution. Irrespective of when they reach menarche, the magic figure of 103 pounds or 46.7 kg also applies. In fact this figure really translates into an average of 22% body fat and it is this fat content that determines whether or not menarche begins.

In today’s world with an obsession about body fat and fitness, many women fail to menstruate because their body fat falls below the critical level. That ancient safety valve that spared women with inadequate nutrient and energy reserves from becoming pregnant still kicks in. Now we know the biochemistry a bit better. Fat contains an enzyme aromatase, which converts a weak male androgen into estrogen, a key female reproductive hormone. Prior to menopause, one third of all estrogen in circulation in females is thus derived. With the onset of the menopause, this rises to 100%. The second key biochemical force to be reckoned with is the protein leptin, secreted from fat. Leptin suppresses appetite and thus the fatter we are, the more leptin we produce and thus the greater the suppression of appetite. We now know from human genetics studies, that a deficiency, relative or absolute of leptin in young girls, totally negates any sexual development. Leptin and related hormones secreted from the adipose tissue form the signal between fatness and fertility sending signals to that part of the brain most involved in sexual development.

The power of body fat levels to shape the female body can reach quite disturbing levels. Young girls, who show a precocious talent for ballet, are known to follow a restricted diet during their strict training to keep their weight as low as possible. Normally, in such young girls, their bone growth occurs at the tips of the long bones where bone is soft and where few blood vessels penetrate this part of the bone. When young girls reach the age of menarche, their bone marrow turns from red bone marrow (making red cells) to a fatty bone marrow and this fat uses the aromatase enzyme to produce estrogen which cause the soft end of the bones to engage with a blood supply, thus ending bone growth. Among female ballet dancers in training, failure to reach the menarche due to excessively low body fat levels, allows the long bones to grow for longer which is why many great ballerinas have spider-like limbs, far longer than would be predicted by their height.

Fat is uniquely important in female biology. And yet, for the most part it remains a very poorly understood tissue. Perhaps a better understanding of the fat and fertility link might rehabilitate fat from simply embarrassing flab to a banner of femininity.

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[1] For this blog I draw heavily on a book entitled “Female fertility and the body fat connection” (Chicago University Press) by Professor Rose Frisch, formerly of the Harvard School of Public Health who was a pioneer in this area

[2] In the early 18^th century, the mean age of males undergoing voice change was 18 years in the choir of John Sebastian Bach. Today, it too has fallen to 13.5 years

Snakes, astronauts and consumer risk perception

In the Holy Trinity of Risk Analysis, that of Risk Communication is the Cinderella of the three while those of Risk Assessment and Risk Management are supreme. The reason why risk communication is so poorly serviced is that scientists and their supporting regulatory structures think that the mere provision of information to the consumer is all that is needed. The consumer is, apparently, worried for the wrong reason because he or she has simply got the facts wrong or confused. All that needs to be done is to educate them. That was how I thought about things until I read the work of Paul Slovik of the University or Oregon. Now, when teaching my students in this area, I tell them the following story. A group of rocket scientists are holding a meeting in a nice convention center. And just as a former astronaut of multiple space trips is about to speak, there is pandemonium as several snakes are discovered in the room, hissing and generally acting in a distinct anti-social manner. The rocket scientists pour out into the lobby led by the former astronaut. Next to their meeting is one of herpetologists, experts in snakes, and they note the concern of the rocket scientists. When they discover it is all due to some snakes in the room, they enter fearlessly and after a while they return smiling, if not tittering, to themselves and explain that these are “usually very harmless snakes and that they are most unlikely to cause any harm at this time of year and at this altitude, longitude and latitude. So, why not go back in and finish your meeting.” If I were there, I would tell the main man where to shove his snakes. Either we get a new snake-free room or it’s sayonara to this convention center. The snake expert is driven by logic while the rocket scientists are driven by emotion. The fears of consumers are emotional and no amount of scientific logic will readily dampen that emotional fear. Hence the mismatch between consumers and scientists.

Slovik points out that whereas “danger is real, risk is socially constructed”. We can start with US studies, which show that educated males trained in science and engineering have the highest threshold for risk. At first this was put down to their proximity to and familiarity with industrial risks and their background training. However, a study that compared male and female US toxicologists showed that females had a lower tolerance of risk. Thus the educational and familiarity aspects were no longer applicable. Men are from Mars and women from Venus. Vive la difference! This comparison was then taken further comparing US and EU male and female toxicologists. The same male-female difference was observed in the EU as had been seen in the US. However, both male and female toxicologists in the EU had a lower threshold of risk compared to their US counterparts. Risk is indeed, socially constructed.

Consumers also diverge from mainstream science in their vision of those aspects of risk that mark the greatest danger to them personally. Paul Slovik cites three main aspects of risk that are used by consumers in constructing a perceived danger to their health namely “dread”, “familiarity” and “control”. First let us look at a public health problem, which has an extremely low population impact but a huge personal impact on those who fall victims to the disease. Creutzfeldt-Jakob disease (CJD) is the human manifestation of “mad cow disease” (BSE) and leads to a dreadful death in humans. So we can tick off the first factor, “dread”. The idea that we develop holes in our brains and die a slow and agonising death is truly dreaded. Few of us know of anyone who suffered CJD or who had a close relative that encountered this disease and so it is utterly unfamiliar to us. The second box is ticked. And finally there is control. How can you know where BSE prions lie? You can’t so you really are at the mercy of lady luck which ticks box three “control”. Let us now compare this fear to that of obesity, which has enormous public health costs and which renders great suffering on large numbers of people. First it isn’t “dreaded”. Obese people can be fit, happy and highly successful and lead a long life! We do not dread obesity and we are also “familiar” with it. Indeed we all know obese people. And finally we can “control” it any time we like by going on a diet and taking up physical activity and we all know people who have lost weight. Thus the consumer sees the greatest danger in areas such as nanotechnology, GM foods, pesticides, additives, CJD, irradiated food and so on. These are dreaded, unfamiliar and out of the control of consumers. The facts that they pose little or no real population risk doesn’t matter. Obesity, sedentary lifestyle, high blood pressure and the like are not seen as something to dread or fear. To add further to this complexity, when consumers are asked about the risk of obesity to society as a whole versus themselves, they see a much higher risk for society as a whole compared to them personally since, irrespective of their weight, they can personally take control of the situation and avoid the problems of overweight and obesity. They of course cannot say the same for the rest of society. They can control themselves whenever they choose to do so, even if society in general cannot.

Slovik makes a critically important point: “Danger is real but risk is socially constructed. Thus, whoever controls the definition of risk controls the rational solution to the problem at hand. Defining risk is thus an exercise in power”. Eco-fundamentalist NGOs are the main definers of risk and they answer to nobody. They are the darlings of the media and the Robin Hoods of the consumers.  Their opposition to a new technology is usually based on some philosophical, moral or social stance. However, they communicate these concerns to the consumer, not by arguing the moral, philosophical or social case but by scaring them with distortions of the scientific facts. The road is risk communication is a long and complex road and it is a road that generally attracts little serious interest in the governmental task of risk analysis.

Your gut is inside out

Recently, I had dinner with my granddaughter Bella (11+) in our favourite restaurant and in the course of the conversation I asked her if she thought her gut was inside her or outside her. She gave me that “Grand Dad, stop being foolish” look. I then challenged with the fact that when we were children, her Uncle Fintan swallowed a threepenny bit (detour to explain) and that when our mother recovered it from his stool, it was in mint condition after a quick wash. “If it was inside him, how come it came out again” I asked only to be given that same look. Out gut is not inside us. It is simply a hollow tube from mouth to anus and in order to get “inside” us you have to cross the gut wall. Grand Dad’s are not always wrong.

Among the organs of the body, the gut is the least loved. It is always associated with the privacy of toilets and from time to time the terrors of food poisoning with trouble at both ends. In fact the gut is not only a very complex organ but it is a very intelligent organ. Not long after conception, a neural crest is formed which will eventually form the human brain. However, it splits and most of the crest goes to the brain while the rest forms the amazing nervous system of the gut. The two are then connected by the vagus nerve. There is more nervous tissue in the gut than in the spinal cord, which carries all the nervous material from the brain to all the organs of the body.  If you think about it, you experience your “gut brain” regularly. Think of the phrases we use: “He hadn’t the guts for it” or “I had butterflies in my tummy” or “I had a gut feeling”. All these phrases point to our awareness of the gut in times of stress. The gut consumes a large amount of the blood flow of the body and when there is trouble ahead, this blood flow falls to enable greater flow to the brain. When the trouble requires us to flee, we may do so having either suddenly emptied our bowels either end, or we flee with no further toilet stops.  There is another reason why our gut needs a brain, which is localised. If we encounter a deadly poison from some bacteria in our gut, it pays to get rid of it very rapidly. Any delay in connecting the toxin to the systemic immune system might just be long enough for permanent damage to be done. Thus the gut induces either vomiting or diarrhea to expel the toxin.

A second major feature of our gut is the colonisation of the gut, particularly the large bowel, with bacteria. Once upon a time, these bacteria were seen as no more than a bioprocessing unit, breaking down the fibrous components of our diet which our digestive enzymes cannot handle. Now we know that these bacteria play a major role in many aspects of our metabolism and our immune system. The human body is warm and moist and thus it attracts bacteria on all outer surfaces most notably the skin and the gut. The latter is not only warm and moist but it is also laden with nutrients. It pays, therefore, for man to have evolved a mutual relationship with favourable forms of bacteria in return for housing them in our gut. In effect, we have a peace treaty with our gut microbes: They keep away pathogens and we house and feed them. There is now very considerable interest in the role our gut microflora play in our everyday health. Their range of genetic material is 100 times greater than ours and some of these genes directly influence our genes in directing metabolism. Their role in obesity is attracting very considerable interest

It is possible to raise mice that have no colonic bacteria, referred to as germ-free. Experiments with conventional and germ-free mice fed an identical high fat diet, show that whereas the conventional animals will get fat, the germ free animals resist this trend and remain lean. These researchers went one step further and looked at a protein found in blood called Fasting-Induced Adipocyte Factor (FIAF). The cells of our gut wall can produce this protein but our normal gut bacteria suppress its manufacture: one of many examples of their genome telling our genome what to do! FIAF blocks the uptake of fats from blood into our adipose tissue stores. By slowing down FIAF release from the gut, the bacteria are now allowing fat to move from blood into adipose tissue. In germ-free animals, there is no such suppression and FIAF blocks the uptake of fat into adipose tissue. To test the link between germ free animals and obesity, the team then genetically engineered these mice to block FIAF synthesis. The germ-free mice now got fat. Thus, in addition to making a good bioreactor for the extraction of maximum calories from food, the gut microbes keep a check on FIAF allowing fat to move from blood into adipose tissue. That our gut bacteria talk to our adipose tissue via FIAF might wake us up to pay more attention to their welfare. 

Parental conflict, genes and obesity

We inherit two copies of each gene in our DNA, one from Mum and one from Dad. There are no exceptions. However, there are about 100 genes, known as imprinted genes, in which one of the parental copies is completely silenced. Effectively, we have only one functioning copy of these genes, either a paternal copy or a maternal copy. Somehow or other, cells know that they carry either the maternal or paternal copy and they behave differently depending on the parental version they carry.

In a normal person, there are about equal amounts of the maternal-only and the paternal-only copies. Mice can be bred to have the usual two sets of DNA but instead of having 50:50 maternally or paternally imprinted genes, we can make all the imprinted genes paternal or maternal. All of these mice contain each and every gene a normal mouse needs, except that for the 100 imprinted genes, they are either all maternal or all paternal. These embryos do not survive which tells us that we need some maternally imprinted genes and some paternally imprinted genes. However, geneticists can modify the normal 50:50 ratio to enrich an embryo in one or the other. The embryos of mice enriched in paternal genes, develop big bodies and small brains. In contrast, mouse embryos enriched in maternal genes, develop small bodies and large brains. This is the first sign of what is termed parental conflict. Daddy wants the foetus to grow big and strong and thus the paternally imprinted genes promote an enhanced flow of nutrients across the placenta and also promote growth of foetal tissue. Mum is responsible for nourishing the growing foetus, so her version of imprinted genes counteracts Dad’s influence, to conserve some of her nutrient reserves for the weaning period and for future pregnancies.

To understand the differences in brain structures caused by enriching a mouse embryo with maternally imprinted genes, we need to see where in the brain are the maternal genes and paternal genes preferentially located. The paternally imprinted genes are predominantly found in that region of the brain known as the hypothalamus, which just happens to be the area of the brain that drives appetite and sex. These are fairly animal instincts. The maternally imprinted genes are mostly found in the cortex. Humans have by far the largest cortex in the animal kingdom and the is the site of the brain which drives intelligence, memory, consciousness, thought, good social behaviour and other higher attributes of human kind. Tarzan may be big but Jane is brighter!

In rare instances, mutations are found in these imprinted genes. Because there is only one copy of each, any mutation is bound to lead to problems. If there are mutations in paternally imprinted genes, a common outcome is the development of the Prader-Willi syndrome. This is associated with a voracious appetite and a lethal level of obesity. If there are mutations in maternally imprinted genes, the child develops the Angelman syndrome. This is associated with a very happy demeanour and a lot of laughter, sometimes inappropriate.

The impact of variation in the balance of maternally and paternally imprinted genes on nutrition continues after birth. There is a protein bearing the code Gs-Alpha, which is very centrally involved in energy metabolism. The gene that encodes for Gs-alpha known as GNAS, is an imprinted gene and in humans, mutations of that gene lead to a condition called Albright hereditary osteodystrophy (AHO), which is associated with short stature and very severe obesity. Again, we see imprinted genes playing a role in growth and energy metabolism. In mice, it is possible to delete either the maternal copy or the paternal copy of GNAS meaning that the mouse has only paternally derived or maternally derived GNAS. These two genetically altered mice are strikingly different. Those lacking the paternal variety will be thin, small, have much less fat, have a higher metabolic rate and are more active.  Those lacking the maternal variety have the complete opposite profile.

What does all this mean for human nutrition and obesity? Firstly, as I have mentioned in previous blogs, obesity has a very strong genetic component. When we come to study this, we must be mindful that the genetic dimension can operate in many ways. We may find that an uneven distribution of the maternal or paternal varieties of an imprinted gene may play a subtle but powerful role. We may find that there are differences in this distribution in different tissues. Finally, we learn that parental conflict is a perfectly normal biological phenomenon.  It only goes wrong when the parental influences are imbalanced.