I thought it might be worthwhile to get away from the day-to-day news for a while and just sort of reflect for a bit on genetics in general.

So our story begins back in the 1850s with the Austrian monk Gregor Mendel, who was a very observant grower of peas.  By cross breeding different varieties of peas and observing and tabulating the characteristics in the next generation he was able to infer the notion of an inheritable trait and describe the idea of dominant and recessive traits.  Before getting into that I suppose I could mention in a quick aside that I remember coming across a write-up once (don’t remember where now) where someone went back and looked at the raw data from Gregor Mendel’s tables and the data actually fit too well. 

That is to say just as one can say that an outlying result is statistically improbable, it can also be improbable to get an almost perfect fit to the frequency distribution of traits.  To put it another way genetics might say that in a subsequent generation there would be three green peas and one yellow, but if you looked at 5,000 families of 4 peas you wouldn’t expect every single one to have exactly three green and one yellow, there would be some that might have three yellow and one green, only on average would it approximate a 3:1 ratio.  So this person when he looked back at the tables calculated that there was, I really don’t remember, but it was something like a one a thousand chance that the actual observed data would fit the laws of inheritance as well as it did.  Now leaving aside that I don’t have the analysis available for you, and whether the person doing that analysis was lying or whether I’m lying and so on and so forth, let’s take for the sake of argument that the person’s analysis of the data is correct.  Well, then was our good Monk Gregor Mendel a liar?  It might be possible that he got a really really good fit to the data by chance, he was a monk;) But there is another possibility namely, that about a tenth of the way into the study he saw the pattern that was developing according to his theories, so there should be let’s say again three green peas and one yellow on average in the next generation.  Well after 50 peas he has 35 green and 15 yellow, the first three peas he looks at in the next group are yellow and the one after that is greenish yellow, or is it yellowish green.  Well really now that I see it in this light it is definitely I would say a yellowish green and so yes a green pea.  Is he lying now?

So here we sort of get more at the original meaning of the  term “bias” in research.    And I mention this not to smear Gregor Mendel’s name, in fact given that I am talking about a half remembered page from a course years ago that I at the moment am too lazy to try and either reference or repeat the work myself it might even be worth looking at is as a fictional account -a sordid tale of secret codes, lies, deception and pea plants in the Catholic church- but really one just meant to illustrate that there is a whole range of possible types of error in medical literature from very subtle biases or things perhaps unconsciously overlooked to outright fraud and cooked books.  Unfortunately, it seems many of the problems nowadays are not in the “how could you not have realized 2.7% of the people in the town were colorblind when you asked them to catalog the peas” as opposed to the “we have ten billion dollars now sign your name here” sort of problem.

This also illustrates the benefits of blinding not only patients but researchers themselves to who is in the experimental arm of a study versus who is in the placebo arm.  To get really off base, I noticed there was a recent study in the news that describes how people matched on certain genetic traits for a specific diet lost something like 5 times as much weight as people who were not genetically matched and now a company wants to sell the genetic test.  I will try to look into this one further, though I haven’t yet, but really the first question that springs to mind is was the study blinded, including the researchers?  One could very easily envision a situation where if the researchers aren’t blinded and have a personal and financial interest in the outcome someone comes in on the genetically matched diet and they say, “my Mrs. Jones, you are looking svelte today, are you still going to the gym? Why don’t I drive you there once we’re through?” versus the a placebo arm patent coming in and, “I know its tough Mrs. Smith, hang in there and it will be over soon, may I offer you some cookies and milk?”  Now I’ll probably get ripped to shreds by the study authors describing how valid a study it actually was and how important, so this one really is fiction, but I will try to look into it.  I better try to get back to genetics now or I may not make it.

Okay, so to continue this discussion there’s a few basic ideas and terms that need to be gotten out of the way early.  So first is the idea of dominant and recessive traits.  As we know everyone inherits one set of traits or genes from each parent for two sets of genes.  If a gene is expressed physically, or phenotypically, as it is called and one has received only one copy of the gene from either parent it is called dominant, if a change is only noticed if the genes from both parents are a particular type it is called recessive.  This may not at first seem that intuitive but if you think about it for a moment it makes sense.  Let’s to make up a crazy, and rather macabre example say there is a gene which instructs cells to make formaldehyde, if someone got just one copy of this gene they would produce formaldehyde and unfortunately die.  This would be a dominant gene.  Now lets instead say there is a gene that codes for a shortened protein involved in the scaffolding of the musculature.  If one got this gene they would make some of the short protein but because they have a second gene there would still be plenty of normal protein around to make normal muscles with and they would be healthy.  It is only if both the genes from the mother and father were for making the shortened protein that the person would be sick.  This is a recessive trait and this example in layman’s terms describes what happens in the disease Duchenne’s Muscular Dystrophy.  For the child to have gotten the disease each parent would have to be a healthy carrier of the gene (or have the disease themselves).

There are many many more layers of complexity to this I’ll try to touch on a few of them that I know of and then there of course are the all the layers we don’t understand, but going back to genetics maybe another good question to look at early on is “what is a gene”?  I mean we use the term all the time, there are all manner of dangers from genetics what at the root level are we talking about.  To answer this we again need to take a side road, this time to Drs.  Watson and Crick and the story of DNA.  Up to the 1940s and a few years before Watson and Crick’s discovery DNA wasn’t thought much of.  Scientists generally dismiss what they don’t understand, turn 180 degrees on a dime and never acknowledge that for decades they were entirely and spectacularly off base.  So because they didn’t know what it did, scientists basically thought DNA was some type of cellular junk and inheritance somehow came about through proteins.  There was one researcher though, who while he didn’t get a lot of notoriety did notice something very odd.  In a replay on the microscopic scale of Mendel’s peas, the bacterium that causes pneumonia, Streptococcus pneumoniae, (aka pneumococcus) can exist either as a smooth, highly virulent, form or a rough, clinically mild form.  So Avery noticed that if he injected dead smooth virulent pneumococcus into mice they were fine, but bizarrely, if he injected dead smooth virulent bacteria into mice and then injected live rough mild pneumococcus the mice died.  And not only did they die but he could recover live smooth virulent bacteria from the mice.  Somehow, the mild bacteria were transformed to the lethal strain from something in the dead bacteria.  He spent many years endeavoring to isolate this “transforming principle” as he called it.  He grew the two bacterias in culture, then used enzymes and chemicals to grind up different portions of the smooth virulent bacteria before seeing what effect it would have on the rough mild bacteria.  By process of elimination he came up with an unusual suspect for his transforming principal, DNA and published his findings in the Journal of Experimental medicine in 1944.

Now Watson and Crick were no dummies, while many researchers didn’t pay attention to Avery’s findings they decided to learn all they could about DNA and especially what its structure was.  Linus Pauling also was no dummy, he was the most respected chemist of his day and has made enormous contributions to science including showing what the three dimensional structure of many proteins is.  There is even today a blog devoted entirely to him, The Pauling Blog. Incidentally Pauling was also a big proponent of mega doses of vitamin C who lived into his 90s.  Pauling proposed a triple helix structure for DNA,  Linus Pauling wasn’t a dummy but he was wrong about the structure of DNA, Watson and Crick noticed a flaw in Pauling’s theory and went back to the drawing board.  To get the right theory though they needed information on the structure of DNA.  If you want to look at something really, really, really, small, smaller than you can see with a microscope, smaller than you can see with an electron microscope you use x-ray crystallography, this is still pretty much true today.  The person who actually did the x-ray crystallography studies of DNA was a scientist by the name of Rosalind Franklin though she did not share in the subsequent Nobel prize.  In any event, having this new data on DNA structure, Watson and Crick were able to formulate a new theory for the structure of DNA, a double helix.  And not just any double helix but one with matching “base pairs” which were strung like steps across a twisting spiral staircase.

There are only four molecules, you can almost think of them as letters in an alphabet, that make up the stairs in the twisting staircase.  Actually we can give them their single letter abbreviations, they are A, C, G and T.  As mentioned, the stair step is made up of “base pairs” that is to say two of these molecules joined together.  Now in order for the stair to be the right width and fit in the staircase it has to match with its correct complimentary base.  So an “A” (Adenosine molecule) must join to a T (Thymidine molecule) if it joined a C or a G it would be the wrong width and break the spiral staircase.  In the same way a C must join a G.

There’s just one more step, uh, twist (darn puns).  Instead of thinking of DNA as a spiral staircase think of it as a zipper.   If you now unzip the zipper you have two halves of the DNA helix.  However, because an A will only join to a T and a C to a G each half can recreate the other missing half by adding the necessary molecules to make the complimentary part of the chain.  And there you have it, the cell can reproduce its genetic blueprint for the next generation.  In probably one of the most understated famous lines in science in the past century, when Watson and Crick described the double helix of DNA in their landmark 1953 paper in the journal Nature they say, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” 

It was either Watson or Crick, I’m nearly certain it was Watson who went on to decide that DNA was too complex to have evolved on earth and must have been seeded here by more advanced races from the center of the galaxy.  I’m also pretty certain I read somewhere where his son spent some time in an asylum.  That would have to be a tough one, your father is a Nobel laureate who discovered DNA and thinks we were seeded here by aliens from the center of the galaxy and you’re the crazy one?

Well this was different.  We are about a third of the way to explaining what a gene is so this looks to be serial installment.  Hope you liked it, if people find this deathly boring you can pass that along too, though I have to admit I rather enjoy writing about things such as this.

Up Next:  The big bad gene!!!   …  well maybe not so bad but you get the idea.