Tuesday, May 31, 2005

Chromosomes and Fertilization

(The link above will take you to the latest NYTimes article on the Korean human cloning project.) (This is installment #2 of a series on cloning and the beginning of life. The first installment is here.)

Now for some details about what goes on in the nucleus of our cells, where our genetic information comes from, and how it is handled normally in the course of cell division, generation of sperm and egg cells ("germ" cells), and in fertilization. This section is long, but I believe that these basic concepts are truly necessary to consider issues relating to cloning and reproduction.

All cells, including bacteria, are constructed according to information that is contained as a type of code on extremely long molecules called DNA. Just as Morse Code contains only two distinguishable elements, a “dot” and a “dash”, so DNA contains only four elements, (A, T, C and G) that spell out strings of three-letter words that each signify a particular amino acid in a sequence. Most cells contain the entire instruction set for the entire organism in a structure called the nucleus, and even those cells that have lost all these instructions (have no nuclei), like red blood cells and platelets, were made from or within other cells that had the whole set.

In mammals and most other complex organisms, these long molecules of DNA are attended by, and in various ways attached to, many specific proteins and sugars whose job is to maintain and interact with the DNA so as to translate its message into actual structures and events in the life of the organism, and this combination of DNA and its associated proteins is called a “chromosome”. The complete set of instructions for each organism is divided into several chromosomes, and the number of chromosomes is species-specific, meaning that any particular species has a certain number of chromosomes, no more and no less. Humans have 23 different chromosomes, numbered 1-22 plus the sex chromosome, which together contain all the information necessary to build and maintain a human being. However, all mammals (actually almost all multicelled organisms) have two samples of each type of chromosome, one from the male parent and one from the female parent, so that for every instruction and every gene (except for a few genes on the X chromosome) each cell has two instances of that instruction or gene, one from each parent. This is a type of protective redundancy; if one of the samples of chromosome #3 is faulty, for example, the chance that the same gene is faulty on the other sample of chromosome #3, from the other parent, is exceedingly small, provided that the parents are not closely related to each other. So, while humans have 23 different types of chromosomes, they have two versions of each type, one from each parent, making a total of 46 chromosomes in each nucleated cell.

A useful metaphor for the contents of the nucleus in each cell is a large library of blueprints, complete with very focused and protective librarians. There is no other reading material…only blueprints. Each blueprint contains the plans for a molecule, which can be either a building-block or structural material, or a molecular machine that manipulates other molecules. Certain molecules that we might think of as “contractor” molecules can come into the library and get copies of each of these blueprints, but only if the librarian molecules allow it. The librarian molecules themselves, of course, were made from blueprints in the library, the complete set of which is called the organism’s “genome”. The blueprints are organized very specifically in certain locations on certain chromosomes, which might be thought of as specific drawers in specific filing cabinets.

Whenever a cell divides, it first makes a complete copy of each of its chromosomes, one for each daughter cell, and utilizes a complex but very reliable process to keep track of each chromosome and make certain that each daughter cell gets only one copy of each chromosome. All the filing cabinets are duplicated, so to speak, and each copy of each one is moved to one end of the library or the other, and then the library divides in half, one for each daughter cell. The only exception is when reproductive or “germ” cells are made, in which case the number of chromosomes is reduced back to only one instance of each of the 23 types, so that sperm and eggs each have only a single version of each chromosome. It is important to realize that there are several “shuffling” steps in the generation of germ cells, so that the 23 chromosomes in any given sperm or egg are a mixed set of genes from both parents, and, statistically, no two germ cells contain exactly the same set of genes. Not only are the maternal and paternal filing cabinets “shuffled”, but the drawers in each filing cabinet are shuffled, so that each cabinet in the end has the same number and type of drawers, but some of the drawers are from Dad and some from Mom. There are no longer any purely “Mom” filing cabinets or “Dad” filing cabinets in the germ cells. When sperm and egg come together, each brings (in humans) 23 chromosomes, so that the resulting “zygote” (fertilized egg) has 46 chromosomes again. The reason mules are infertile is that horses and donkeys have different numbers of chromosomes, so that the resultant mule does not have a “matched set” of chromosomes and hence cannot make useable germ cells from its odd number of chromosomes.

When an adult human makes a germ cell (actually, a woman’s eggs are all made while she is still a fetus in her own mother’s womb, but a man makes sperm continually), each germ cell therefore should have 23 chromosomes, one of each type. Some birth defects, such as Down’s syndrome and XYY syndromes, occur because one of the germ cells had an extra chromosome, so that the resultant individual has 47 chromosomes instead of 46.

Let us consider the germ cells. These are properly cells that are part of the human being that made them; every one of their chromosomes is a copy of one of the human’s own chromosomes, their substance came from the cells that divided to make them. They are hence “human” cells, and cannot be thought of as belonging to any other organism than the one that produced them. Most of these cells die without issue; they do not reproduce, and most of them never meet a germ cell of the opposite sex to form a new individual. A male produces millions of sperm a day, all but three (in my case) dying without producing a new individual, and a woman likewise “wastes” all but a few of her eggs.

Fertilization refers to the merging of the nuclei of the sperm and the egg to form a single nucleus, containing a set of 46 chromosomes, 23 pairs, one member of each pair from each parent. For millennia, this occurred only within the body of the woman, usually in the fallopian tubes, as a result of normal sexual intercourse. Now it can occur within the woman as a result of artificial insemination, or outside the woman “in vitro” (“in glassware”). “In vitro” fertilization is similar to the manner in which fish and amphibians fertilize their eggs; the egg is outside the female, and the sperm is dumped over the egg to fertilize it. The egg chemically attracts the sperm; the sperm have no “eyes”, and therefore rely upon chemical signals from the egg in order to locate it. The egg is swarmed by thousands of sperm that work to penetrate its outer layers, and as soon as the first sperm penetrates a threshold, the egg raises a membrane-like structure to repulse all the other sperm so that only a single male nucleus can fuse with the egg nucleus to make 46 chromosomes. My point here is to note that the egg is not “passive” in fertilization, but interacts with the sperm. A normal egg and a normal sperm “do something” specific to effect fertilization. We will see that this is not the case in cloning.

The fertilized egg is called a zygote. At this time, since we cannot duplicate either sperm or eggs, every egg and every sperm is unique, no matter how obtained and no matter where fertilization takes place. Therefore, every zygote, at this stage, is unique. We will note that this is not the case in cloning.

(Next: Determination and Differentiation, here)

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