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.
You are a collection of cells, literally trillions of them, each with a specific design and function. With a few exceptions, cells have a basic architectural design, most of the time being depicted as looking like a fried egg cooked sunny side up. However, in reality they are three dimensional beings, so it might be better to think of the average cell as a golf ball that you’ve cut across its midline. The “white” of our cell model is the body of the cell, and here are found many specialized areas called organelles that do particular jobs, much like our own internal organs have specific jobs as well. The “yolk” of our cell model is called the nucleus, and in this compartment there lies the object of our affections, the chromosomes.
Chromosomes were first discovered at the end of the 19th century by a German biologist named Walther Flemming. Flemming was looking at cells under a microscope and got the idea to use colors to dye the cell to make it easier to see things. The idea must have worked better than anticipated since he at once began to see spaghetti looking things in the nucleus that dyed a very deep color. As is the fashion, he named these entities chromosomes which is Greek for “colored bodies”.
Chromosomes are one of the more dynamic faces of Nature; they have to be, since they are responsible for the passing on of the Baton of Life that we call reproduction. The number of chromosome in the cell nucleus differs somewhat from species to species. We human have 46 chromosomes; dogs have 78; alligators 32; cabbage plants 18.
Your chromosomes are both the governess and chauffeur of the most important molecules in your body; DNA. Like any blueprint, DNA needs to read in order for the work order to be constructed. Now, DNA is a long, long molecule. If it were completely unraveled it would be about six feet long, yet so thin that it would be invisible. If the entire DNA, in every cell of your body, was stretched out and laid end-to-end in a straight line, it would reach to the sun and back over one thousand times.
I think an effective way of describing the dynamic qualities of the chromosome is to use a few metaphors. My older daughter likes to knit, so we often visit the knitting supply shop in town for fresh yarn. Yarn usually comes wrapped in skeins, a length of yarn wound around a reel. Most yarn comes in lengths of 80-150 yards. One of the nice things about buying yarn this way, rather than just as one long unwound string, is that you can put it under your arm and walk to the car. This is certainly better than tying a knot to the rear bumper and pulled the unwound string all the way home. Thus, the first important lesion of chromosome dynamics; if you’re going to reproduce you’ve got to stuff that entire DNA into a very small, tight package. Chromosomes are just that: tight packages of DNA.
On the other hand, it is very difficult, if not downright impossible to knit anything if the skein of yarn still has the paper label wrapped around it. In order to use the yarn, you have to unwind it. That’s the formula: when the cell needs to use DNA to get information about how to make a protein, it has to unwind it. When it needs to reproduce, or turn off the DNA information flow, it needs to concentrate and condense it.
DNA is packaged and concentrated by special proteins termed histones. This concentrated DNA is called chromatin, which is the DNA plus the histones that package DNA within the cell nucleus. Chromatin structure is also relevant to DNA replication and DNA repair.
Histones are very cool bead-like proteins that spool the DNA in a way that makes it either tighter or looser, sort of like the cardboard around which our skein of yarn is wrapped. Histones respond to changes in their structure by tightening the DNA wrap or loosening it. Whenever a cell needs to access the genetic information encoded in its DNA, the histones on the section of the DNA that is needed undergo a chemical reaction called acetylation by which a molecule called an acetyl group is stuck on the histones, causing them to relax and unravel. When business is concluded for the day, special enzymes come along and chomp off the acetyl group cause the histones to become de-acetylated, which makes them tighten up again, sending the DNA in the region back to its resting state. Think of it like this; when your DNA needs to work its histones chow down on acetyl groups for breakfast and they do yoga; when it needs to reproduce or shut down, the histones lift weights --the strain of which causes the acetyl group to pop out of their mouths.
Only until recent times have we understood this mechanism, and of its supremely paramount importance: That it is used by the environment to influence gene function and that influence, for either good or bad, can be passed on as inheritance. Amazingly, we not only inherit the genes from our parents, but state of histone acetylation of the genes as well. Thus, the histone acetylation patterns of the genome are a prime mechanism of epigenetic inheritance, along with DNA methylation.
Scientists have given each human chromosome a number, according to its size; thus chromosome number 1 is the largest, then number 2, etc. Chromosomes come in pairs, one from each parent. So there are 23 pairs, for a total of 46 in us humans. Numbers 1-22 are non-sex chromosomes called autosomes, and pair 23 contains the X and Y sex chromosomes.
In the few minutes it has taken to read up to here, this, around 400 million of your red blood cells were depleted and replaced, consistent with the set of genetic instructions contained in your DNA. This is where the genetic code comes in.
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?
I'm just back from a site visit to the Dolce Conference Center, scene-to-be of the upcoming IFHI 2009 Conference and Certification. What a facility! If you've been to the Buttes for 2005 or 2007 prepared to get gob-smacked! The premises (a former monastery) are just gorgeous this time of year. The intimacy of the lecture halls combined with the terrific AV capabilities of the facility already have my mind running in overdrive. I think it was very smart to top the attendance at 125. This will insure that everyone feels that they are a real part of the event.
Unfortunately, despite the fact that the conference is three weeks away, I'm told that all available rooms at the Dolce Conference Center have been taken. We have a few seats still available for the day sessions, and if anyone plans to register from this point on, we can book them at the nearby Double Tree Inn and the Dolce will bus these folks back and forth.
Anyway, if you want to attend IFHI, even at this late point in the process, contact IFHI Conference Services and maybe they can work something out for you.