Genetics of Original Sin (9 page)

Base pairing does not only account for DNA's duplex structure, but also for its replication. The chemical system that assembles a new DNA chain using an old one as template automatically inserts T in front of A in the template, and vice versa, G and C likewise calling for each other (
fig. 5.2
).

A very similar base-pairing code rules the replication of RNA, which closely resembles DNA, with the only chemical differences being that deoxyribose is replaced in the common thread by ribose (hence the name of
ribo
nucleic acid, or
R
NA) and the base T is replaced by U, a close relative that, like it, pairs with A. In addition, in nature, RNA rarely exists in double-helix
form. It is usually made of a single thread, most often folded into a tangle of loops closed by short double-helical joints linking complementary stretches situated at distinct sites of the same thread.

Fig. 5.2.
DNA replication.
The top half shows part of a DNA double helix, unwound so as to expose the joining of the two complementary strands by base pairing: A joins with T by means of two hydrogen bonds; G joins with C by means of three hydrogen bonds. The bottom half pictures synthesis, guided by the same base-pairing mechanism, of two new complementary strands on the separated strands of the original DNA. (Knowledgeable readers will note that this schematic diagram by the discoverer of DNA replication leaves out the fact, discovered after the picture was drawn, that the two strands are replicated in reverse directions.) After A. Kornberg, in
Molecules to Living Cells: Readings from “Scientific American”
(New York: W. H. Freeman, 1980), 270–280.

It is very probable, as we have seen in
chapter 2
, that, in
the origin of life, RNA preceded DNA as replicable bearer of information and, therefore, that replication developed first for RNA. Today, this ancestral phenomenon takes place only in cells infected by certain viruses (the polio virus, for example) that possess an RNA genome. Everywhere else, replication concerns DNA. Historically, however, RNA replication was probably the first manifestation of base pairing, inaugurating what may well be the most fundamental process in the whole history of life on Earth.

Indeed, base pairing has turned out to be the dominant mechanism for information transfer throughout the living world, from the origin of life to the present day. It does not just rule DNA and RNA replication, but also the transcription of DNA into RNA and the opposed process of reverse transcription, the synthesis of DNA on an RNA template, which is carried out by certain viruses, for example the causal agent of AIDS. Base pairing also plays a fundamental role in the many interactions between RNA molecules that take place in the translation from RNA into proteins and in many other processes. It is the key mechanism in the universal language of life.

Reproduction remained molecular until the appearance of the first cells. After that, DNA replication had to be followed by doubling of the cells that contained the DNA, so that each daughter cell would be left with one of the two DNA copies. This doubling first occurred by simple division and, later, in eukaryotic cells, by a much more complex process called mitosis. We won't go into the details of this process, except to note that it involves rodlike structures, called chromosomes, bearing
the DNA molecules that make up the cell's genome. Each cell division is preceded by duplication of the chromosomes, itself intimately linked with replication of their DNA content.

Such mechanisms sufficed as long as organisms remained unicellular. Once the first multicellular organisms appeared, a new reproduction mechanism evolved. Barring some rare exceptions, such as the reproduction of certain plants by budding, all multicellular organisms originate from a single mother cell that, by division and differentiation, gives rise to all the cells of the organism, and is called
totipotential
for that reason. It might be assumed, a priori, that this mother cell would arise in a parental organism, either from a differentiated cell returning to the totipotential state by “dedifferentiation” (
fig. 5.3
) or, as proposed by the German biologist August Weismann (1834–1914), from a continuous line of totipotential cells dividing asymmetrically to give rise, on one hand, to a totipotential cell that perpetuates the line, called “germ plasm” by Weismann, and, on the other, to a cell committed toward the formation of differentiated cells and eventually leading to the new organism (
fig. 5.4
).

Such mechanisms are not involved in the reproduction of organisms, but they play a role in other phenomena of considerable interest. Thus, the Weismann hypothesis accounts for many cases of cell renewal. In the bone marrow, for example, the various blood cells arise from a continuous line of so-called
stem cells,
which divide asymmetrically to give one daughter cell destined to differentiate further into a red blood cell or one of the various types of white blood cells, while the other daughter cell remains a stem cell. Similar processes take
place in most other organs, thereby replacing damaged cells. Even brain cells, which had long been seen as irreplaceable, can be generated by this mechanism. The possible therapeutic use of such “somatic” stem cells (from the Greek
soma,
body) for tissue repair has evoked enormous interest in recent years, especially because their use does not encounter the same ethical objections as does the use of embryonic cells, which is condemned by a number of religious groups because it involves the destruction of a potential human being.

Fig. 5.3.
Hypothetical model of reproduction from a somatic differentiated cell that dedifferentiates into a totipotential cell leading to a new organism.
This phenomenon is not involved in the reproduction of organisms, but it is, to a certain extent, in cancerous transformation and, especially, in artificial cloning (see
chapter 15
).

As to dedifferentiation, it occurs, for example, in the conversion of normal cells into cancer cells, which are thereby almost returned to the status of rapidly dividing embryonic cells. Dedifferentiation has also become a subject of burning interest in relation with artificial cloning techniques. Recently, headlines were made by the announcement that certain differentiated
cells can be induced by relatively simple means to return to stem cell status, another potential breakthrough in the production of stem cells for therapeutic purposes. We shall return to these important issues at the end of the book (see
chapter 15
).

Fig. 5.4.
Weismann's theory.
August Weismann postulated a continuous germ line from which successive generations of organisms branch out laterally by asymmetric division. The model does not apply to the reproduction of organisms but accounts for the formation of somatic cells from pluripotential stem cells.

The mechanism almost universally used for reproduction by multicellular organisms involves, not one, but
two
cells. It is sexual reproduction (
fig. 5.5
). In this process, the mother cell from which a new organism is destined to arise is the product
of the fusion of two distinct cells, most often with very different properties. In technical jargon, these cells are called “gametes” or “germ cells,” their properties are distinguished by the terms “male” and “female,” their fusion is known as “fertilization,” and the product of this process is called a “fertilized egg cell.”

Fig. 5.5.
Sexual reproduction.
This diagram illustrates the maturation, by way of meiosis, of haploid male and female gametes from diploid mother cells, and the formation of a diploid fertilized egg by fertilization of the female oocyte by the male spermatozoon. Note that cytoplasmic organelles, including mitochondria, are eliminated in the course of sperm maturation but are conserved in the course of oocyte maturation. This phenomenon is taken advantage of in the phylogenetic procedure based on the comparative sequencing of mitochondrial DNA (see mitochondrial Eve,
chapter 9
).

One wonders how sexual reproduction can ever have developed, as it implies a phenomenon that, according to every prediction, should have had a lethal effect, namely the multiplication of chromosomes, whose number doubles with every generation due to the fusion of two cells. This drawback was eluded by the development of a special kind of mitotic division, called
meiosis,
in which the double, or
diploid,
number of chromosomes inherited from the fertilized egg is reduced back to a single, or
haploid,
set in the course of germ-cell maturation. Thus, when two (haploid) gametes, male and female, join in fertilization, they generate a (diploid) fertilized egg, containing two sets of chromosomes. All the cells of the organism that arise through the development of the egg are likewise diploid, with the exception of the cells destined to become gametes. These cells undergo meiosis in the course of their maturation and become haploid, ready to repeat the cycle. This alternation between haploidy and diploidy is called
alternation of generations.

Surprisingly, sexual reproduction, with its attendant passage through meiosis, occurs in the three multicellular lineages, plants, fungi, and animals. Development of such a complicated mechanism independently three times defies plausibility. One is thereby led to look for its origin in protists. Unicellular eukaryotes do indeed sometimes engage in this kind of reproductive fusion, especially under conditions of stress. Even prokaryotes occasionally practice what is known as conjugation, a process in the course of which two such cells exchange genetic material, thus creating new genetic combinations.