Diabetes Metab. 2009 Sep;35(4):262-72. Epub 2009 May 5.
Intestinal microflora and metabolic diseases.

Serino M, Luche E, Chabo C, Amar J, Burcelin R.

Recent advances in molecular sequencing technology have allowed researchers to answer major questions regarding the relationship between a vast genomic diversity-such as found in the intestinal microflora-and host physiology. Over the past few years, it has been established that, in obesity, type 1 diabetes and Crohn's disease-to cite but a few-the intestinal microflora play a pathophysiological role and can induce, transfer or prevent the outcome of such conditions. A few of the molecular vectors responsible for this regulatory role have been determined. Some are related to control of the immune, vascular, endocrine and nervous systems located in the intestines. However, more important is the fact that the intestinal microflora-to-host relationship is bidirectional, with evidence of an impact of the host genome on the intestinal microbiome. This means that the ecology shared by the host and gut microflora should now be considered a new player that can be manipulated, using pharmacological and nutritional approaches, to control physiological functions and pathological outcomes. What now remains is to demonstrate the molecular connection between the intestinal microflora and metabolic diseases. We propose here that the proinflammatory lipopolysaccharides play a causal role in the onset of metabolic disorders.

Increasingly, studies are showing that changes in the microflora content of the digestive tract can be linked to metabolic illnesses, including type II (adult onset) diabetes and obesity. Blood group and secretor status play an important role in conditioning the overall characteristics of the digestive tract, including influencing the appearance and frequency of many strains of bacteria.

Pathol Biol (Paris). 2008 Jul;56(5):305-9. Epub 2008 Jan 30.
Role of gut microflora in the development of obesity and insulin resistance following high-fat diet feeding.

Cani PD, Delzenne NM, Amar J, Burcelin R.

A recent growing number of evidences shows that the increased prevalence of obesity and type 2 diabetes cannot be solely attributed to changes in the human genome, nutritional habits, or reduction of physical activity in our daily lives. Gut microflora may play an even more important role in maintaining human health. Recent data suggests that gut microbiota affects host nutritional metabolism with consequences on energy storage. Several mechanisms are proposed, linking events occurring in the colon and the regulation of energy metabolism. The present review discusses new findings that may explain how gut microbiota can be involved in the development of obesity and insulin resistance. Recently, studies have highlighted some key aspects of the mammalian host-gut microbial relationship. Gut microbiota could now be considered as a "microbial organ" localized within the host. Therefore, specific strategies aiming to regulate gut microbiota could be useful means to reduce the impact of high-fat feeding on the occurrence of metabolic diseases.

It has been known for quite a while that the colons of obese individuals are considerably longer than non-obese people. Now the idea is increasingly being advanced that obesity is, in part, related to greater "energy harvest." This would appear to throw the time-honored "just eat less and exercise more" argument right out the window and verify the common observance that many overweight people do not consume any greater amount of calories than many non-obese people.

J Pediatr Gastroenterol Nutr. 2009 Mar;48(3):249-56.
Intestinal microbiota during infancy and its implications for obesity.

Reinhardt C, Reigstad CS, Bäckhed F.

Sahlgrenska Center for Cardiovascular and Metabolic Research/Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.

Obesity is a worldwide epidemic, threatening both industrialized and developing countries, and is accompanied by a dramatic increase in obesity-related disorders, including type 2 diabetes mellitus, hypertension, cardiovascular diseases, and nonalcoholic fatty liver disease. Recent studies have shown that the gut microbial community (microbiota) is an environmental factor that regulates obesity by increasing energy harvest from the diet and by regulating peripheral metabolism. However, there are no data on how obesogenic microbiotas are established and whether this process is determined during infancy. The sterile fetus is born into a microbial world and is immediately colonized by numerous species originating from the surrounding ecosystems, especially the maternal vaginal and fecal microflora. This initial microbiota develops into a complex ecosystem in a predictable fashion determined by internal (eg, oxygen depletion) and external (eg, mode of birth, impact of environment, diet, hospitalization, application of antibiotics) factors. We discuss how the gut microbiota regulates obesity and how environmental factors that affect the establishment of the gut microbiota during infancy may contribute to obesity later in life.

One of the great chin-scratchers of modern physical anthropology revolves around blood type, in particular why most indigenous populations of the New World have such incredibly high percentages of the gene for type O. Sometimes, especially as you move south of the modern US-Mexico border, the percentages almost reach 100%.

Since almost everyone agrees that human habitation of the New World began with migrations out of the Siberia, across the Bering Sea, and the population on the Russian Asiatic side shows no similar high percentage of type O; if anything the percentage frequency of the type O gene drops as we move further and further north and east. Several theories have been advanced to explain the apparent 'Bering Sea Bottleneck'.

The most often suggested is the genetic drift theory. The basic idea behind genetic drift is easy enough to understand. If you flip a coin two hundred times, there is a very good chance that your results will be somewhere close to 100 times coming up heads, and another 100 times coming up tails. Indeed, the more you flip a coin, the more likely (given that you have an honest coin) the results will be 50% head and 50% tails.

However, suppose that you instead only flipped the coin seven times; would it not be feasible on any given Sunday to flip five heads and two tails? Sure it is. That is how Las Vegas stays in business. Genetic drift is like that: A small population may have an uncharacteristic gene distribution simply because the genetic coin did not flip enough to have things even out.

So the Genetic Drift Theory of the 'Bering Bottleneck Type O Anomaly' posits that a small band of folks swam, walked or boated over the Bering Strait, and because their numbers were so small, the genes for A and B did not come along with the coin flip. This small number of colonist determined the future gene pool for the continent due to their exerting a 'founder effect'.

It's not a bad theory, except that in order to accomplish this, the numbers of Asian immigrants to the New World must be very small; along the order of a dozen or less, so that there is an even slight statistical chance that they could all be type O. However, even if the original colonizers of the New World numbered, say ten or eleven, the odds of those entire ten or eleven colonist being type O is about one in a thousand. Even if the number of colonists is dropped to five the odds only drop to one in thirty-two. (1) And that also assumes that there was one boatload or band of colonists, when common sense tells us that there must have been numerous attempts, though perhaps not all successful, to migrate to the New World.

The second theory is that of Natural Selection, which a lot of people equate with evolution, but it's not. Natural selection posits that perhaps a mixture of all blood types were part of the original migration, but for some reason, probably infectious disease, the type A and type B colonists died out. Of the two, Natural Selection is perhaps the stronger theory since there a definite likes between ABO type and susceptibility to small pox, syphilis, E. coli and tuberculosis, all of which probably killed lots of people back then.

However, as any honest exterminator will tell you, it's hard to kill them all.

A.E. Mourant addressed this issue in his book Blood Relations

"Like the absence of B in the Australian aborigines, the lack of B in the northern zone and of A and B in the southern zone raises a problem of world-wide importance. Was the B gene totally absent from the original populations from eastern Asia that ultimately reached Australia and America, or was the gene lost on the way? If so, was this due to genetic drift in relatively small isolated populations, or to natural selection? Early blood-group workers suggested that when man left Asia for Australia and America mutations for the A and B genes had not yet occurred. However, analogous if not identical genes occur in the higher apes at least, and so are several million years old. In the light of the discussion of O frequencies in Europe it is not difficult to see how, as a result of the elimination of A and B fetuses of O mothers, first the gene B (which is rarer than A) could have tended to disappear, and then A itself."(2)

Now, it has been know for a while (3) that human and primate ABO genes are somewhat analogous, let's just say that they are similar enough for our purposes, which is to say that the individual genes for A, B and (by default) O are 'old'. However, does it automatically lead us to assume that just because genes share a long history, does that mean we can assume that they will always exist in the percentage numbers? Of course not, we just say that with Genetic Drift: percentages change.

With apologies to Edward Tufte, let's take a look at the snazzy graphic I just did:

What you are looking at is the northeast corner of Asia and the northwest corner of North America at the Bering Strait, across and under-which one day your kids may be able to drive their cars. Not surprisingly, the colors of the map mean things: For example, the darker green the land is colored, the higher the frequency of the gene for type O; the lighter the color, the lower the percentage (less type O genes)

Now, first of all, note that these are indigenous populations, so the modern-day Alaskans and Siberians don't figure here that much here. What sticks out at you? Yup, there is lots of O gene the further east (the right side of ther map) you travel! But what else? Normally we might expect the trail of O genes to drift nicely along, but in our map the distribution is bi-modal: The incidence of O gene is higher at both ends of the map and lower in the middle. You can see that by looking at the bar graphs below, which not only looks at the relative 'percentage if each percentage' but also the percentage of land versus water: Each bar graph is actually a snapshot of one of the sixteen 'slices' of the map, the black lines.

So if anything, the more constricted that land mass became, the less you find the type O gene.

Interestingly, look at the red numbers on the map. They are the percentages of type B gene. Notice as well that the Asian side of the Strait has some of the highest percentage of Type B gene on the planet. What about on the American side?

Virtually no type B gene.

Now, to me this implies that there may well have been two waves, a 'First Wave' that contained very high percentages of type O gene and which had a relatively easy time getting across the Bering Strait (which may well have still been a land bridge) and who created the 'Founder Effect' in America, and a 'Second Wave' somewhat higher in Type A and much higher in Type B which followed but got stymied by the ecological changes and the closing of the land bridge.

So what I think is that both the Genetic Drift and the Natural Selection theories are correct, but I'm more inclined to move both of their occurrences with regard to blood type further back in time and much further west. In that case, rather than having crossed before the advent of the genes for A and B, our first American colonists would have walked across before the rest of Asia had a chance to recover from the results of its own initial 'flip of the coin.'

By which time there was no more walking there.

1. L. Luca Cavalli-Sforza. Genes People and Languages. University of California Press, 2000

2. Mourant, AE. Blood Relations, Blood Groups and Anthropology. Oxford University Press, Oxford, UK 1983.

3. Saitou N, Yamamoto F. Evolution of primate ABO blood group genes and their homologous genes. Mol Biol Evol. 1997 Apr;14(4):399-411.

Growing up in Brooklyn I remember many exciting and fun filled trips to Manhattan --or as anyone from Brooklyn calls it, “The City.” One of the features I always looked forward to seeing was a huge advertisement for a paint company that featured a can of paint pouring itself over a globe of the world, its byline proclaiming “We Cover the Earth with Our Paints.”

Excepting the obvious question as to why anyone would ever want to cover the world in it, paint is not a bad metaphor for how most scientists viewed inheritance before Mendel, it being a sort of “blended essence” --a mix of the features of both mom and dad, much like how we might combine white and black paints to make gray. In the late 1800s Charles Darwin proposed a mechanism of inheritance by means of gemmules, imaginary granules or atoms which are continually being thrown off from every cell or unit, and circulate freely throughout the system. Yet Mendel’s research showed that it was nothing of the sort; being in fact much more digital, like how a computer makes all sorts of interesting stuff out of what are essentially zeros and ones. Mendel’s theory nixed that notion completely, although after a while things started to be observed that appeared to indicate that genetics wasn’t all that black and white, on and off after all, but I’ll save that for a later story.

I’ve married a blue eyed woman, and have two daughters. The first daughter has brown eyes just like me. Simple enough: My brown-eyed alleles squash my wife's blue-eyed ones. However, my second daughter has greenish-hazel eyes, much lighter than mine or her sister, but certainly not bright blue like those of my wife, so it would seem like a little blending is going on over there after all. Eye color is not a simple dominant-recessive trait, although knuckle hair and tongue rolling are. The eye color trait is what geneticists call polygenic, which simply means that it is not decided by one single gene. In order to account for my younger child’s green-hazel eyes, we have to add other factors to the mix.

My wife is pure Irish on her mother’s side and a mix of Slovakian and Hungarian on her father’s. Hungarians have the highest percentage of green eyes of any population, close to 20%, so something in my wife’s blue-eyed world (the blue-eyed allele of her Hungarian father) produced a variant that refused to role over and die, but instead made alliances with other genes --including a recently discovered one that may go back to the Neanderthals--- that slips green eyes and red hair in between things, ultimately producing my younger daughter’s wonderful green eyes. Given that, you'd think I'd get the tongue rolling gene and she the knuckle hair, but alas, the results are quite opposite.

Many traits are polygenic, and when when added to the tremendously under-appreciated epigenetic effects on gene expression, explain why we have never found a single gene for diabetes, or cancer or Alzheimer’s disease. If it were that simple, we’d have had the answers to these questions already.

Another type of inheritance is very close to my heart. The allele (the set of alternate genes for any trait) for type O blood is recessive to the alleles for type B and type A. Again using my family as an example, biologically I am type A blood and my wife is type O. My daughters are both type A blood, so we know that they must have received a type O allele from mom and a type A allele from me. Their genotype for ABO blood type is A/o (recessive alleles are usually depicted in lower case, dominant in capitals, and genetic things are usually rendered in italics).

If I was instead type B blood and had provided a type B allele, the children would have type B, as type B is dominant to type O as well.

But here is where things get interesting. What happens if you were to receive one type A allele and one type B allele? Why, you would be blood type AB! The reason behind this is that although both B and A clobber O, they strike a tentative truce between themselves and split the kingdom and declare a dual monarchy. This is called co-dominance. There are not many instances of co-dominance in genetics, and ABO inheritance is almost always given as the example.

You may well ask why, if type O is recessive to types A and B, why hasn’t it disappeared, leaving only A and B to slug it out, and eventually producing a world of only type AB people? The reasons and proofs for this are mathematical, so I won’t bore you with them, but suffice it to say that if a population is large enough, and the individuals in that population tend to mate randomly, and there are no other major influences (such as one type being more resistant to an infectious disease), after one generation the gene pool will stabilize and reach a sort of equilibrium.

Since there is such a huge amount of o allele in the human population (so much so, in fact, that even though it is the recessive allele, individuals with type O blood constitute the majority of most populations around the world) it will keep propagating itself, whereas the type you’d have though would be replacing everyone else by now, AB, comprises at best about 2% of the population.

Most people probably have a negative concept of mutation, spawned by a slew of admittedly great science fiction. However, it might surprise you to learn that that vast majority of mutations, at least the ones that get incorporated into our genetic heritage, are not lethal and often don’t do very much at all. For example, let’s again turn to our trusty blood types. As we will explore in more later on in this book, genes are chunks of DNA that do things, like code for specific proteins. Although DNA is an incredibly long molecule (if all the DNA in all your cells was unwound and placed end to end it would produce a string capable of reaching to the sun and back several times) it is composed of a simple string of four repeating nucleotides abbreviated A,T,C and G. The sequence of these four repeating nucleotides is what contains the instructions for the protein.

The difference between having the gene for type A blood or type B blood is a variation of a mere seven letters out of the total of 1,062 that make up the entire gene. We even know exactly where they differ: letters number 523, 700, 793 and 800. If you are type A blood, you have C,G,C,G in these locations, whereas if you are type B blood you have G,A,A,C there instead. Yet however slight this difference is, it is enough to cause a major problem if you were to receive the wrong blood in a transfusion. These are called point mutations because they are a simple one-letter misspelling in a gene, unless as in the case of blood type it is a consistent variation that is inheritable, in which case it is called a polymorphism.

The type O gene mutation is even more interesting. It derives from a frame shift mutation. If you are type O you may be surprised to discover that rather than having a difference of letters, like A and B, you're just missing one letter, number 258, entirely.

So hopefully by now you are comfortable with the notion that mutations are just part of life, unless of course you are unfortunate enough to have gotten a lethal one (and there are many) which probably would never have allowed you to get so far in life as to be able to read this blog. Many, if not most, of these mutations are spontaneously terminated while the sufferer is still an embryo in utero. Virtually all of the well-known genetic disorders are semi-lethal.

There are may causes of mutations, including viruses and radiation, but the most common cause is the simple fact that when our cells reproduce, they must make a complete copy of there DNA, and sometimes the copies don’t turn out so great. Think about the photocopy of that great joke that circulated around the office cubicle the other day. If it was barely legible, with bloated letters that ran one into the other, it was probably because someone made a photocopy of the original, which was quite likely a photocopy of the previous copy. Each time a copy was made of a copy, the writing was degraded a bit more.

Genes are like that. Often as we get older, we tend to get more and more of this “photocopy effect”. Perhaps what was once a word string of CAG became CAA. Even if it is copied correctly, it will be CAA from there on. Perhaps not unexpectedly these mutations are called “copying errors” and given the enormous amount of cell division that goes on over the course of a lifetime it is the real surprise is just how good of a job we do at it.

Fascinating presidential election; certainly a very unique and historic outcome. It will be interesting to see --given the perilous state of affairs we find ourselves in-- whether 2008 is also the first presidential election in which (come January) it is the winner rather than the loser who demands a recount.

Science is fact-based, but scientists can sometimes be charmingly naïve. One of the most common ways they display this naiveté is the coining of politically correct euphemisms. So, instead of the negatively charged term “race” you sometimes see the phrase “mutually inbred ancestral groups” which, at least to me, sounds even worse.

Despite the gloss, we at least now have a framework to allow us to collect and categorize those genes and polymorphisms that show different frequencies between races.

Called “Ancestry-Informative Markers” (AIM) this category of genes includes blood groups, markers of pigmentation and other SNPs that distinguish between races but don’t always result in some visually detectable difference. A collection of AIMs that distinguish African and European populations contains over 3000 highly differentiated SNPs. An example of an AIM gene is called “Duffy” and it codes for the Duffy blood group. A variant codes for a Duffy blood group type (Duffy Null allele) that is found 100% of Sub-Saharan Africans, but occurs very infrequently in other races. Interestingly, like some of the hemoglobins, this variant has been known to provide some resistance to malaria infection.

Looks like it’s time for another one of my semi-autobiographical digressions.

By the mid 1970’s I had completed the required college level classes to allow my application to a college of naturopathic medicine, since by then I had determined to follow in the footsteps of my father and enter this (at the time) obscure and curious profession. This was a time of great difficulties for this tiny healing art; more naturopaths were retiring and dying than entering the schools, and the future of the profession indeed looked rather bleak. There were tiny glimpses of hope however at least in the one remaining school, where the “Old Guard”--most often gentlemen who had learned their trade in the 1920’s and 30’s—- were giving way to “Young Turks”; aging hippies and other political rejects from the 1960’s. Unfortunately this was not at all harmonious, and at the time I was to apply we heard that the school was in uproar, as one faction or another had locked it opposite out, changed the locks, kidnapped the files –you name it.

So instead, we looked across the Atlantic, to The British College of Naturopathy and Osteopathy, and upon acceptance, I duly relocated to the “Post-Swinging London” of the late 1970’s, which as it turned out was in a rather downtrodden phase, with escalating energy prices, joblessness and at times civil unrest. This was the era of the “Urban Punk” and “Anarchy in the UK”. One only had to look around to see heart-wrenching tableaus of its more hypocritical aspects: Homeless folks sleeping against under banners proclaiming the Queen’s Silver Jubilee.

Jobs were scarce, and as a foreign student, it would have been virtually impossible to get the few that were available. I had a small stipend, and made a “few quid” doing some odd jobs. Nonetheless the dire economic circumstances forced a series of relocations, each typically one level further down the social level than the one prior. Yet these were happy times, with great friendships and new experiences, more so when I landed at the charming London neighborhood of East Finchley, a quiet suburban backwater about five miles from London City Center.

Again, as long before, a pleasant and affluent suburb, East Finchley in 1977 was the infrastructure and architectural equivalent of a visit to an eccentric, wealthy, emphysemic great-aunt. While sipping tea and hearing of the “old days” you might gaze upon the fine wood details of the hand made furniture or the anonymous faces in the dulled and dusty photographs on the wall, often in the poses of stern solidity or in an exuberant moment of victory. It would seem that only the passage of time could dull the greatness of all that past glory.

If Great Britain was at its mercantile and military zenith by the beginning of the 20th century, even more so was its pre-eminence in the rapidly growing fields of genetics, statistics and evolutionary biology. In 1890, at the pinnacle of the gilded greatness that was Victorian England, doughty old East Finchley witnessed the birth of one the greatest of her sons, a man who in the words of a one historian was a “genius who almost single-handedly created the foundations for modern statistical science.” His name was Ronald Aylmer Fisher.

The son of a successful businessman, Fisher was had a precocious intellect, and because of his poor eyesight learned mathematics without the use of paper and pen; leading to a marvelous ability to visualize problems in geometrical terms, and to forever frustrating both teachers and students by being able to produce mathematical results without setting down the intermediate steps.

Fisher published an important paper in 1918 in which he used powerful statistical tools to reconcile what had been apparent inconsistencies between Charles Darwin's ideas of natural selection and the recently rediscovered experiments of the Gregor Mendel. Among many and varied later accomplishments, it was this singular achievement that gave birth to modern evolutionary science. This was completed with the publication of The Genetical Theory of Natural Selection in 1930.

In 1943 Fisher accepted the Chair of Genetics at Cambridge University. Photographs invariably show a bearded, white haired, bespectacled man, with very thick glasses owing to his extreme myopia. More often that not, a billowing pipe accompanies the picture. He was addicted to the crossword puzzles of the London Times, which in characteristic fashion he filled in only those letters where the words crossed each other. His eccentricities, termed by his student “Fisherania,” though sometimes embarrassing, where more often the source of great entertainment to his friends.

Johann Wolfgang von Goethe wrote that “Certain flaws are necessary for the whole. It would seem strange if old friends lacked certain quirks.” Certainly Fisher had his flaws. He was an early and enthusiastic proponent of Eugenics, a social theory advocating the improvement of human hereditary traits through various forms of intervention, including sterilization, prenatal testing and screening, genetic counseling, birth control. Fisher was also opposed to the developing argument that smoking caused lung cancer, partially due to his dislike and mistrust of Puritanism and perhaps also due to the solace he had always found in his pipe.

Although he would rapidly wash his hands of the more dunderheaded students, Fisher was a inspirational mentor to his acolytes, many of who would go on to stellar careers of their own in the field of genetics, statistics and anthropology. These ranks included the previously mentioned A.E Mourant, who did work with Fisher on the epidemiology of Rh blood group genetics; Robert Race and Ruth Sanger (who my friend Gerhard Uhlenbruck once described as 'Being married-- but to other people.') themselves later on co-authored an acclaimed textbook on blood groups; A.W.F. Edwards and Luca Cavalli-Sforza, who studied the “relatedness” among various population groups.

In continuing my work on developing The Individualist Wiki, again and again I come up against the greatness of one single man: William Clouser Boyd.

William C. Boyd.

• Boyd wrote the first textbook of immunology.
• Boyd discovered the blood type specificity of many lectins.
• Boyd coined the word 'lectin.'
• He was one of the first 'paleoserologists', using lectins to trace the blood type distributions of many populations around the world. Boyd was the first to document that blood group substances could be recovered intact from physical remains of graves, such as from mummies.
• With Isaac Asimov, he wrote a book for the general public which was one of the first to attack the notion that race was a scientific fact.
• He developed antibody techniques, such as precipitation and flocculation, and applied them to blood group serology.
• He was among the first researchers to recommend the use of magnesium salts in the immediate aftermath of heart attack.
• Boyd wrote some pretty good science fiction (under the name "Boyd Ellanby" ).

Every time I venture into something, be it ABO blood group immunology, lectins in foods, anthropology, and a slew of immunology techniques, this guy was there first. It's a pity nobody really knows about him.

Best serologist, ever.