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.

Drones, queens and genes

We inherit our genetic code from our parents and from cradle to grave that genetic sequence is immutable. We all know that forensic medicine can take any part of the human body, however small, and sequence the DNA, thus obtaining our absolutely unique genetic code. If every part of the human body contains the full sequence of DNA inherited from our parents, then why is your ear not your nose? What makes the different parts of our body different from one another is that the inherited sequence of DNA is “tweaked” so that genes that are not needed are turned down or off and those that are needed are turned up. Effectively, nature gave us a genetic dimmer switch which cannot change the sequence of genes but which can change the extent to which individual genes are expressed. By far the most striking example is the queen bee. All bee larvae contain the exact same genetic code obtained from the queen and thus they are clones. When a queen passes her sell by date so to speak, the worker bees prepare a new queen. From the thousand of cloned larvae, they select one and the wrap that larva up in a secretion from their throat region. That secretion is Royal Jelly and it contains a very unique balance of nutrients. Most importantly, it contains a protein known as Royal Lactin[1]. The effect of this is that the larva treated to Royal Jelly emerges as a queen bee, which, while sharing the exact same genetic code as the worker bee, is physiologically vastly different. Indeed up to one third of all the genes that are associated with the bee brain are differentially expressed (up or down regulated) in the queen bee. Queen bees live for years while worker bees live for only weeks. The queen bee will uniquely produce 2,000 eggs on a summer’s day while worker bees are sterile. This modification of gene expression is called epigenetics and it is of enormous importance in human nutrition.

During  life in our mother’s womb, nature’s genetic dimmer switch gets to work. Without changing a single aspect of genetic sequence, it switches up some genes and switches down others. It does so to make sure that the new born baby has its genetic profile made to measure for the external environment into which it enters at birth. There are two ways to look at this phenomenon, the first of which is physical. John Hammond, a famous UK animal scientist reported in 1938 on a study, which crossed the very large Shire horse with the very small Shetland horse. When a Shire stallion mated a Shetland mare, the offspring had the physical proportions of the Shetland mare. Vice versa, when the Shetland stallion mated a Shire mare (with help I assume!), the offspring had the proportions of the Shire mare. Even though all of the foals born had 50% Shire and 50% Shetland genes, their life in the womb determined their birth size. The size of the uterus in gestation over-rode the genetic inheritance. This was among the first studies to show that our inherited genetic sequence is subject to significant up- and down-regulation during pregnancy. The second factor that emerged as a major determinant of pregnancy modulation of gene expression was diet. It began with historical studies that linked birth weight and length to the risk of many diseases in adulthood. Thus for example, in adulthood, the risk of developing high blood pressure was shown to rise dramatically among those who had a lower than average birth weight and a higher than average placental weight.  When this data began to emerge in the early 1980’s it was regarded as almost heretical by nutritional epidemiologists for whom all chronic disease could be explained by poor eating habits. In time, the evidence grew and animal experiments bore out the theory. Today, we absolutely accept optimal nutrition in pregnancy is essential to minimize disease later in life.

Pregnancy is not the only period where nutritional factors can cause the expression of our genes to change with life long effects. The second vulnerable period is the first 2 years of life. (This period, combined with the duration of pregnancy,  is referred to these days as “The first 1000 days”). During the first 2 years of life, diet can play a role in permanently altering both our physique and our cognitive function. If growth is impaired during this period in any sustained manner, then the person will be permanently stunted, that is too small for their age. Stunting is widespread in developing countries. During the first 2 years of life, our brains grow both in size and in complexity. In adults, the brain consumes about a quarter of all calories consumed. In infants, this figure rises to nearly three quarters of calories consumed. If children are inadequately nourished during this period, their cognitive function is permanently reduced.

To understand why nature has given us this gene dimmer switch we need to consider its evolutionary advantages. In pregnancy, the biological profile of the mother, in which diet plays a powerful role, lays down a permanent imprint on gene expression. If times are frugal, the birth weight falls and the baby is programmed for a frugal existence. If that child grows to be an adult in a very non-frugal and obesogenic environment, then they cope poorly such that chronic disease rates rise. Thus we adapt to the biological environment prevailing during pregnancy in the expectation that that will prevail. In times gone by, that adaptive mechanism had a great evolutionary advantage. As regards the evolutionary advantage brain development in the first 2 years of life, that lies in the ability to absorb the culture into which the child is born. Chinese babies learn to speak Chinese and to absorb Chinese culture. Each culture needs that time to imprint all of its values into the new born. The brain of a foal is hard wired at birth such that instantly, the foal stands and runs with the herd. No schooling is needed.  Horses just haven’t evolved as man has with its “plastic” infant brain.

When the human genetic code was sequenced, the “genohype” predicted great medical miracles. We now know that sequence is one thing but how that sequence is expressed is what makes a huge difference and we know that a balanced optimal diet will lead to the optimal changes I gene expression. We now also know that one of the main public health nutrition challenges is maternal nutrition. It is a challenge that the high priests of healthy eating are unhappy with because it distracts them from their prevailing wisdom with which they are very happy.

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[1]http://www.dbbe.fcen.uba.ar/new/contenido/objetos/KamakuraNature2011Royalactin1.pdf

Markets and malnutrition

In 1985, the rock star Bob Geldof organised Live Aid to raise money to combat famine in northern Ethiopia. Some 8 million persons suffered sever famine of whom 1 million died. What wasn’t known at the time was that in southern Ethiopia, there was ample food. So great was the glut that prices fell by 80% and subsequently, almost 300,000 tonnes of maize was left to rot in the fields.  The co-existence of food shortages and food gluts comes down to a failure of markets and during this period and for decades afterwards, the Washington suits of the World Bank and IMF were adamant that governments stay away from price support and agricultural subsidies. Leave it all to the markets was the theory. That happily has now been abandoned and there is a clear recognition that markets only work when the proper infrastructure exists.

African agriculture has a long way to go to make real progress. Only 7% of arabale land in Africa is irrigated compared to 45% in Asia. Road density is 6 times greater in Asia than Africa and fertilizer use is 7 times higher in Asia. Food production per capita has stagnated in Africa and fertilizer use, a useful measure of the confidence  farmers have in agriculture, has fallen. The food import bill for Africa is now double what it was  2 decades ago.

African farmers tend to think locally when it comes to taking their crops to market and typically they trade only with a radius of 8 to 10 km of their farm. They trade with dealers they know and trust. However, they are always left with the same problem. They have no idea what price they are likely to receicve for their crops. They cannot know that, for example, this year many farmers have decided to grow some crop such that when they turn up at the market, the price is rock bottom. Last week the price might have been much higher but they have no way of knowing these important issues. Farmers may even take a pig to he market to find no buyer. Food commodities change hands four times on average before they reach the end user and, apparently, each time the food is re-branded by being put into the buyers sacks! Of course at each trading occasion there is a level of risk because just as the local farmer has no market knowledge, that also appies up the line.

Eleni Gabre-Madhin gave up her job as a senior economist at the World Bank to return to Ethiopia to build Africa’s first commodity exchange. This blog builds on her TED presentation[1].  The Ethiopian Commodity Exchange (ECEX) is housed in a spanking new building in Addis Ababa. It has created a highly integrated system to bring buyer and seller together. For the buyer, the system provides complete confidence that the material being purchased is of the grade and standard that is being paid for. For the seller, the system provides a knowledge of the commodity price in real time. This is achieved by using mobile telephony as well as the use of purpose-built internet cafes. ECEX has for the first time in Ethiopia, introduce a grades and standards sysytem so that farmers can see the advantage of inward invstment in their enterprise to attain a higher grade and thus earn a premium price. Farmers can lock in prices through forward contracts and use future prices for planting decisions and for inward investment in their farms. Farmers can now sell across time and distance and buyers dont need to see the product since it is certified in one of the 20 ECEX warehouses dotted around the main areas of agricultural output.  Ethiopia produces more grain than South Africa and is the second largest producer in Africa. The establishment of ECEX takes the risk out of trading because it imparts detailed and instant knowledge to buyer and seller. With the growth and integration of such commodity exchanges south of the equator, the day when the northern hemisphere dictates price to the south will disappear.

Will another Live Aid concert be needed? Well, while Africa learns to help itself, it will continue to need aid to combat malaria and HIV and to ensure that the commodities grown in this highly fertile land are available to its citizens at optimum levels, when and where they are needed. Slowly, Africa is learning to help itself.

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[1] http://www.ted.com/talks/elene_gabre_madhin_on_ethiopian_economics.html

Banning food colours. Bad science ~ Bad legislation

Philippus Aureolus Theophrastus Bombastus von Hohenheim was born in 1493 and, perhaps not surprisingly, changed his name to Paracelsus. Celsus was a Roman physician who gave the element zinc its name and this pompous Swiss German medic decided to re-name himself  ‘Equal to Celsus’. He is famous for his dictat: ”Sola dosis facet venum”, which translates from the Latin into “The dose alone makes the poison”. In other words, everything is toxic at the right dose and under the right circumstances. Pure Alpine air is highly toxic if a certain dose is injected intravenously. The exact dose remains unknown since no such experiment has ever been done but you get my drift, I hope.

In 2007, a group of researchers from Southampton University published a paper in the prestigious medical journal, The Lancet, showing that a cocktail of food additives (6 colours and 1 preservative) caused hyperactivity and reduced cognitive function in children.  The study was well conducted. It used a placebo (identical in look and taste to the active cocktail) and it used a cross over design, meaning that each child received the active cocktail for a week and at another occasion the placebo for a week. They used two age groups, 3-year olds and a group of 8-9 year olds. The study was analysed by two important committees of experts, the UK Committee on Toxicology and the European Food Safety Authority (EFSA). Both gave their approval.

The consequence of this publication was very serious. The EU introduced a law mandating that a food containing any one of the 6 colours had to be labeled to state that the food contains a colour, which “may have an adverse effect on activity and attention in children”.  The findings were championed by the UK Food Standards Agency (FSA), which pushed for the ban. However, EFSA held the view that the effects of the food colourings on children's behaviour were small and the significance for children's development and education uncertain. The FSA view prevailed within the EU regulatory process and the ban came into effect.

Without doubt, this entire affair calls into question the entire approach that the EU and its agencies to the application of science to risk assessment. Lets just think about linking evidence to policy. No study has ever been completed in which any ONE of the 6 colours, on their own, had any effect on childhood attention deficiency.  Now one could respond to that and say that there may only have been one active colour so lets just label them all. But what about the 7^th additive used, the preservative, benzoic acid. That was excluded from the ban because it reduces the risk of food poisoning whereas colours are just colours. Now suppose the active ingredient was benzoic acid? There is a second flaw to the study, which is relative to the issue of dose as raised by Paracelsus. According to the authors in the paper, the doses were chosen because they represented normal exposure of children to food additives in UK children. Thus they used as their reference intake, the equivalent of three 56g bags of sweets for the younger children and double that for the older ones. Now 4 x 56 is 224 grams per day and at 4 calories per gram, that translates into almost 900 calories. This would mean that UK 8-9 year olds were deriving about 50% of their calories from sweets. That would quite simply lead to wholesale nutritional deficiencies since sweets are just pure sugar with some fat – no minerals or vitamins. Now, at the time this paper was written, the official UK data showed that in this age group, the contribution of all sugar confectionary was just 7%. How could they have got this dose so wrong? Why didn’t the FSA and EFSA not challenge the dose aspect of the paper?

In Ireland, we conduct food intake surveys for different age groups and what makes our approach unique is that we always collect the packaging of all foods consumed. These are photographed and the ingredients list entered on to a database. So we set out to ask if among teenagers and children, there was even one eating occasion among the 118,000 such occasions during the 7-day survey period, when all 7 additives were consumed. The answer was zero. In other words, no child or teenager in Ireland ever, even on just one occasion, consumed all 7 additives at the one time. We then went on to see if the levels of colours used in the Southampton study were ever achieved in our samples. Even at the top 1% of consumers of any colour, the intakes came nowhere near the levels used in the Lancet study.

The ban has come into force and most food producers have complied well ahead of the build up period. The public wasn’t screaming for this and the vast majority doesn’t even know it happened. But it satisfied the worried well who lobby the European Parliament and it was grist to the mill to their anti science approach to risk analysis. But some day the development of bad legislation based on bad science will come back to haunt them. 

Weight loss new year resolutions

Across the globe, millions of people will commit themselves to a New Year resolution to lose weight. Almost all will fail. The 5-year cure rate for obesity is less than the 5-year cure rate for the worst cancer, a view articulated by the American Medical Association’s Council on Scientific Affairs almost 25 years ago. If dieting were a drug, it would have failed the regulatory process given that it is generally not a long-term success. Yes, there are successes but they require life long adherence to a restricted food intake.  Basically speaking, when we gain weight and retain that gain for some time, it is recognised biologically as a new norm. When we lose weight, that same norm is constantly there and constantly wishing to re-establish itself. Losing weight is easy. It’s retaining that weight loss which is huge challenge. Rule number one in weight management: Whatever your weight is now, don’t gain any more. That is a battle you can win. 

There is a second battle you can win and that is to get fit and in so doing, you will negate all of the adverse effects of overweight and obesity.  There is a wealth of literature to show that it is better to be fit and fat than slim and sedentary. Physical activity will restore blood pressure to normal and will restore the ability of the body to handle glucose thereby reducing the likelihood of obesity-related diabetes. Physical activity enhances a sense of wellbeing, something that is readily lost when people gain weight. One of the very best teaching aids on the health benefits of physical activity is available at http://www.youtube.com/watch?v=aUaInS6HIGo.

Obesity and overweight remain among the major challenges to public health nutrition that we face today. The food industry and particularly the fast food industry are the focus of attention. And whilst food intake must be a part of the solution, so too must physical activity. The problem is that we have constructed a way of life that is sedentary and we have designed a built environment to support that. One of the most inspiring exponents of physical activity is Professor James Levine from the Mayo Clinic. He has championed the concept of NEAT: Non Exercise Activity Thermogenesis.   Basically, most of the energy we consume is dissipated as basal energy needs for the functioning of our heart, lungs, kidneys, brains and son on. We also dispose of some energy in digesting and absorbing food but this is minor. After basal activity comes exercise activity thermogenesis. This area of energy expenditure is planned as a walk, a game of golf, a jog, a swim and so forth. Levine has defined another activity (NEAT), which is effectively “fidgeting” or physical activity that is not seen as intentional physical activity: picking up the phone, walking to the bathroom, standing up to give a presentation. So, lying down at complete rest costs 5.4 kilojoules (Kj) per minute. That goes up to 5.6 if seated at complete rest. Sitting but “fidgeting” raises the figure to 8.2. Now lets take a look at the same activities while standing. Standing motionless has a cost of 6.1Kj.  Standing but fidgeting now increases the value to 10.3. Walking in a stop start fashion as in many work places raises the value to 13.7. Thus simple acts of physical activity make a huge difference to energy expenditure. Levine published a scientific paper in the very prestigious journal Science in which he overfed volunteers with an additional 1000 calories per day. Before the study and during the study, ALL volitional activities were controlled and minimized. He used advanced techniques to measure body fat (DEXA scans) and energy expenditure (stable isotopes). Having overfed these people for 8 weeks with an additional 1000 calories, all subjects gained weight. However, as I’ve explained before Blog of November 14^th last) , genetic variation will mean that some people will gain more weight than others. But in what fraction of energy expenditure was between-subject variation related to gain in fat mass? Not basal metabolic rate and not the thermogenesis of eating. There was a powerful negative correlation between NEAT and fat gain. The more fidgety the person, the lower the weight gain. Levine has gone on to design a unique office, which facilitates NEAT. The telephone is as far from the desk as possible. The desk can be elevated to facilitate standing and he has also designed an award-winning desk[1], which has a two-mile an hour treadmill option to facilitate NEAT (http://store.steelcase.com/products/walkstation/).

We have as much obligation to tackle our obesogenic built environment, as we have to tackle our food intake. However, architects and ergonomic designers of comfortable offices are not as attractive a villain as is the corporate food sector.

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[1] Invention of the Future Award from NASA, and the Innovation Award at the World Fair