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.

Although just about everyone knows something about DNA, I’d like to take a few moments to introduce you to RNA, the real power behind the throne.

Protein represents what biologists call phenotype – the living, breathing, metabolizing part of life. DNA is information. Other than acting as a blueprint and occasionally remembering to replicate itself, it doesn’t have a single real world obligation. It is RNA that acts as the bridge between DNA and protein, translating the message of DNA into the reality of proteins. All the basic functions of the cell require RNA. Copies of the desired DNA gene message are first copied onto one type of RNA, which is then read by a machine composed in part by some more RNA to create proteins by linking amino acids which are delivered by another type of RNA.

Let’s start the second part of our story with the sweet, if short life of Messenger RNA, or mRNA.

At a certain point in its life, the cell may get an urge to make some sort of protein or enzyme. Let’s say that you have developed an untidy habit, like smoking cigars. As anyone who has ever tried one can tell you, the first experience with nicotine is usually far from pleasant, with dizziness and nausea the usual end result. This reaction occurs because the new smoker has yet to habituate himself to the poisons in the cigar and has not yet developed a way to detoxify and break them down. Over time the continued smoking of cigars sends an environmental message to cells of the liver telling them that they need to make higher levels of the enzymes used to detoxify tobacco toxins. This message (“hey, he’s trying to kill us out there!”) travels to the cell nucleus, where special machinery locates the section along the DNA that contains the gene to produce these detoxifying enzymes, snips it open and unravels that part of the DNA to expose the blueprint.

At that point an enzyme called RNA polymerase comes along, reads the DNA code and makes an RNA copy by linking together similar building blocks (a stretch of RNA is similar to DNA except that RNA is almost always single-stranded and uses the nucleotide Uracil instead of Thymine). This is called “transcription” and just like a court stenographer transcribes the court proceedings, so RNA transcripts the proceeding necessary to make a protein. The RNA strand, called Messenger RNA, (mRNA) is then extensively primped and tweaked to clean it up and get it just right. From here it is about to embark on the ride of its life.

Once everything is set to go, the mRNA is shot through the one of the many pores which act as gates between the cell body and the nucleus. Once out into the cell proper it is carried to the real workhorses of protein synthesis, the ribosomes. Using a railroad analogy, you can think of a ribosome as a dispatcher in the rail yard, whose job it is to assemble an entire freight train. Each time the phone rings the dispatcher gets his next order:

“Fetch the Baltimore and Ohio flatbed with the Honda Hybrids on it. Attach it to the Union Pacific 3985 locomotive.”

“Next, locate and attach the milk tanker from Happy Cow Farms.”

And on and on, until you have one of those interminably long freight trains that take twenty minutes to pass by the railroad crossing as you desperately try to get to the airport.

Just like our rail dispatcher, ribosomes get the information from messenger RNA, by zipping along the code like an old fashioned ticker-tape, reading the code called 'codon triplets' to determine which amino acid to fetch, then linking that amino acid to the prior one, and fetching the next instruction, etc. until it gets a stop message.

In this job the ribosome is assisted by a different type of RNA called Transfer RNA which acts like a crusty old rail yard worker, bringing the appropriate amino acid to the ribosome. At some point the protein is finished up and released, and the messenger RNA decomposes back to the basic building blocks of DNA and RNA, called nucleotides, and ready to do it all over again.

From there the sky is the limit. Proteins are interesting in a lot of ways but perhaps most interesting in their folding tendencies, a molecular origami if you will. Depending on the amino acid sequence and length proteins will fold into a myriad number of complex three dimensional shapes, and it is these shapes that give them their unique powers over the environment.

For example a protein of a certain shape may function as an enzyme, taking sugar molecules and attaching them together, turning single sugars onto cellulose, an important dietary fiber. The protein that results from our string of amino acids might be an insulin molecule, helping to control the owner’s blood sugar, or even a protein that helps DNA do its job, perhaps even part of another ribosome!

As I said, the sky is the limit.

The RNA Queen is so basic to life that many scientists think that perhaps life originated with it, and not with DNA: That DNA came along later as a way to 'memorialize' the work of RNA.

Because I attended a Catholic grammar school which was private and did not receive any state or government funding, we were often dispatched on extenuated and cheerless forays out into the public in a quest for its nickels and dimes. This usually included the sale of various candies or 'chance books,” a cluster of five or ten tickets which entered the owner into a drawing of some sort, for a variety of possible prizes.

Never mind that this same public (due to the limitations of spatial geography and the ambulatory capacities of a ten-year old) was already paying through a myriad of other schemes to keep their kids in this very same school. Typically after suitable introductions had been made and accompanied by sufficient eye-rolling and entreaties heavenward, the wallet would be procured and another book of chances sold. Usually, I’d take the opportunity to remind them of what a wise investment they had made, only to be greeted by the sobriquet “Sonny,” and the dismissal of a future possibilities with an off-hand “I’ve never won anything, and I’m not very lucky.”

From that point to this, I’ve always marveled when people tell me that they aren’t very lucky, since of course it is not true. Just wondering about your unluckiness, marks you as being among the luckiest of all. As a matter of fact, you have won one of the greatest raffle prizes of all time; at odds so astronomical so as to be incalculable. You’ve won the raffle of life.

Just think. Your parents first needed to have come from genealogical lines that survived through all the plagues, wars and accidents of time. Second, they needed to be in physical proximity, so as to come into contact with each other. Third, they had to be attracted in such a manner as to stimulate (hopefully) the urge for procreation in each other. Fourth, they had to be in that particular mood at just the time when the team “up at bat” sperm and egg-wise was you. Fifth, the sperm that carried the genetic information from your father had to compete with millions of other sperm in a race that would make the New York City Marathon look like a trip to the store for a newspaper. Sixth, even upon winning, that sperm had to find an egg at just the exact time when it was ripe for fertilization. Finally, after fertilization, the embryo had to travel through the Fallopian tubes and implant in the uterus where it developed form the cluster of cells into something that would eventually grow to the point where it could take care of itself.

So who among us is unlucky?

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.

Perhaps a list of his partial accomplishments will demonstrate:

• 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.

Welcome to The Weekly Transfusion, 1.4 for the week of April 6, 2009.

Editorial: Medical journal statistics for autodidacts

You can become a better consumer of health information if you take the time to read the research source material (i.e the scientific publication in which the original claim was made). Of course if the study is technical you can see quite a bit of jargon that you may or may not understand. However many medical terms are widely understood and where you bump up against the odd phrase or name that you don't comprehend, there are usually places on the Internet where you can find simple, easy to understand explanations. Wikipedia is actually pretty good for this type of look-up, as long as the subject at hand is not controversial.

However, methodology and monikers aside, most scientific studies distill down to a simple testable premise which is easily understand by almost anyone. Did the medicine work? Was the association between this gene and that disease valid? Past asking the question, what is needed next is to look at and gauge the value of the answer. Surprisingly, even though this is usually some sort of statistical type of answer (and most laypeople are not well versed in statistics) once you know what to look for, you'd be amazed just how easy it is to evaluate most studies.

Most research studies feature a subsection entitled Results or Conclusions. It is here that the results are most often given. There are many way of calculating statistical significance, but the premise is quite simple: What is the chance that the thing we just observed/ hypothesized was random versus the odds of it being due to the relationship we are studying. This is known as probability and in statistics is usually called the P value. To find out just how significant the results of any study are, just look for the P value. The smaller this number is, the less likely the results occurred by chance. Put another way, the lower the P value the more likely you'll want to view the results as significant or important.

The great Ronald Fisher viewed P values as measures of the evidence against a hypotheses, sort of like how a prosecutor presents a case based on exceeding the jury's sense of 'reasonable doubt.'

Now for the secret (OK, not so secret) key to taking control of the medical facts in your life: The standard level of significance used to justify a claim of a statistically significant effect is when P is equal to or less than 0.05; in essence, a one-in-twenty chance that the result had nothing to do with your hypothesis.

For better or worse, the term 'statistically significant' has become synonymous with P<=0.05.

So when looking at any published results, always look for the P value and if it is greater than five cents on the dollar (0.05) you'd probably want to ignore that results (unless the premise of the article was that the researchers failed to show a relationship, which is of course just another type of observation; however, these types of studies usually don't make it out of the researcher's file cabinet) or take a look at the methodology behind the study (scientists are human; studies can be poorly designed and the conclusions derived may not have been the best test of the hypothesis).

So, P<0.05 means the results are significant, but just barely. Good enough to convict, but also likely to send a few innocent people to jail as well, since there are still strong indications that the hypothesis fails to account for the whole of the facts. Personally I like to see P values of at most 0.01-0.02 before I get excited about anything I'm reading. However I do make exceptions for studies with small numbers of participants, or if the we're dealing with an herb or vitamin where the effects studies may be slight or slow to surface.

Oftentimes you'll see P values with lots of zeros. That means they've found a more statistically reliable result. For example, the P value in the following article is P<0.001. This actually means that there 1 in a 1000 chance of the result being a random occurrence and a 999 in 1000 chance that the result was related to the premise of the study.

Just remember, look for at least a P<0.05. That means the results were statistically significant. Beyond that the more zeros you see in the P value, the better. Try your new-found statistical powers on the articles below. Look for the P values in the studies. What do they signify?

Now that you can evaluate scientific material at its source, you'll be less likely to fall for the 'man bites dog' con-jobs that are all too commonly reported in the news or as what passes for scientific discussion these days.

Resting heart rate as a low tech predictor of heart problems in women

In a large, diverse group of postmenopausal women, resting heart rate was an independent predictor of coronary events, with higher heart rate associated with greater risk. The relation between resting heart rate and risk of coronary events was stronger in younger postmenopausal women than in older ones. Resting heart rate did not independently predict stroke.

In general, age, body mass index, and saturated fat consumption were higher and cardiovascular risk factors such as hypertension, diabetes, smoking, hypercholesterolaemia, and depressive symptoms more prevalent in women with higher resting heart rate, as was self reported nervousness. Physical activity and alcohol use were inversely related to heart rate (both P<0.001), and heart rate was lower in women who used postmenopausal hormone therapy than in those who did not (P<0.001).

Article Link

Comment:

One can't argue that this is about as low tech a predictor of future health problems as one is likely to find. It has already been shown that resting heart rate predicts coronary events in men. For women however, the relation between heart rate and coronary events or stroke has been uncertain. The study broke the participants into groups including a 'high heart rate group' whose heart rate was greater that 76 beats per minute and 'low heart rate group' whose heart rate was greater than 61 beats per minute. The association with 'coronary events' (aka heart attacks and death). This association appears stronger in women aged 50-64 than in those aged 65 or older

Being overweight makes you age faster

Obesity and weight gain in adulthood are associated with an increased risk of several cancers. Telomeres play a critical role in maintaining genomic integrity and may be involved in carcinogenesis. Using data from 647 women ages 35 to 74 years in the United States and Puerto Rico (2003-2004), we examined the association between current and past anthropometric characteristics and telomere length in blood. These findings support the hypothesis that obesity may accelerate aging, and highlight the importance of maintaining a desirable weight in adulthood.

Article Link

Comment:

A telomere is a region of repetitive DNA at the end of chromosomes, which protects the end of the chromosome from destruction. When DNA needs to be read (to replicate itself, or generate RNA so as to begin coding proteins) a problem arises in that the enzymes that duplicate the chromosome and its DNA cannot continue their duplication all the way to the end of the chromosome. They need a blank area to 'park' much like the cassette tapes of days past had white 'leader tape' at their front and the back so that the tape head did not start in the song itself. Unlike cassette tape, every time DNA reproduces, a bit of the white leader tape, the 'telomere' at the end, is frittered off and has to be replaced. Telomeres and replenished by an enzyme, the telomerase reverse transcriptase. Telomeres protect a cell's chromosomes from fusing with each other or rearranging - abnormalities which can lead to cancer - and so cells are normally destroyed when their telomeres are consumed. In the women studies for this article, those having a higher body mass index (BMI) in their 30s were associated with shorter telomere length in their 40s (P < 0.01).

I suspect some of this association is epigenetic, and points again to the fact that the GT5 Warrior epigenotype may well need to get their weight profile optimized early in life and be increasingly calorie conscious as they age.

Vitamin D, adult-onset diabetes and metabolic syndrome

Vitamin D is a potent immunomodulator that also enhances the production and secretion of several hormones, including insulin. Vitamin D deficiency has been associated with increased risk of type 1 diabetes. Glycemic control and insulin resistance are improved when vitamin D deficiency is corrected and calcium supplementation is adequate.

Article Link

Comment:

More and more information is surfacing about vitamin D (actually more of a hormone than a vitamin) and insulin resistance. Studies consistently show that vitamin D levels in both North America and the Pacific are typically lower than optimal. In the USA , most vitamin D intake from foods is provided by fortification. Canada and New Zealand have fewer fortified choices, and intakes are correspondingly lower. The mechanism of action of vitamin D in adult onset (type 2) diabetes is thought to be to its role in the control of plasma calcium levels, which help regulate insulin synthesis, but may also be the result of vitamin D stimulating the insulin secreting (beta) cells of the pancreas directly. If you have a history of metabolic syndrome or adult onset diabetes in close family members you may want to consider adding vitamin D to your supplement regimen. However, make sure that you do it in partnership with a nutrition professional.

One from the vaults: Mom's blood type can influence child's risk of Strep (1978)

In a prospective study of maternal genital colonization with streptococci at the time of delivery, epidemiological data, including blood type (ABO group), were recorded for the 1,062 patients studied. Blood type B was found in a statistically significant (P <.005) higher proportion of patients colonized with streptococci (28%) compared with the total population (16.4%)

Article Link

Comment:

Evidence suggests that probiotic supplementation does change the vagina flora of women. Since it appears that the route of transmission of Streptococcus is from the birth canal, physicians should recommend probiotic supplementation for pregnant women beginning 3-4 weeks prior to expected date of delivery as a way to prevent streptococcus infection in neonates. This should be especially emphasized if the mother is either blood group B or AB.

This study again illustrates the fact that some of the best ABO correlation studies are outside the purview to today's physicians, most of whom would tell you that any research from 1978 is better suited to a history class than to any thing taught in medical school.

Since Mother's Day is fast approaching, also remember that recurring otitis media (ear infections) is strongly associated with the child's mother being blood type A. In fact the correlation here is quite startling. Children of mothers who are blood type A are twenty seven times more likely to get a second ear infection within one year of contracting the first. To give you an idea of just how strong this association is, look at the chart below to compare the RR (relative risks) of a few other disease/ lifestyle links.

Update: IfHI 2009

Just a quick word to the wise about the IfHI Conference, Norwalk Connecticut, June 5-7. We had run out of available rooms at the Dolce Center Campus. However 10 additional rooms have just been made available. Unlike previous conferences, where attendees could book almost to the day of the event, IfHI 2009 looks like it will be completely booked by the middle of May, a full month before the event. If you are planning on attending, either for certification or just personal enrichment, please make your reservations ASAP, especially if you want to stay overnight on campus.

Until next week.