Genetics of Original Sin (8 page)

Fig. 4.1.
A schematic view of metabolism.
Foodstuffs provided from outside enter the metabolic network, where they are either degraded with the production of energy or used for syntheses. The energy freed by the degradations serves to sustain the syntheses, as well as the other forms of work carried out by the cell. Synthetic processes serve to form new cell constituents to satisfy the needs of growth and repair, reserve substances, which are stored, and secretion products, which are discharged outside, together with metabolic waste products.

It is a dynamic, perpetually changing network, in which
the circulation of matter is subject to an equally complex set of automatic regulations that constantly adapt to each other the velocities of the reactions involved. In it, certain spots are the targets of outside influences that allow the network to adjust to changes in the milieu or to respond to hormonal or nervous messages. Many poisons and drugs act by intervening at one or the other site of the metabolic network, by inhibiting a reaction, for example, causing jams that may paralyze the entire network.

Metabolic networks vary with cell types, which owe their particular properties to those networks. But they include certain central pathways that are common to a vast majority of cells, such as those known by experts under the names of glycolytic chain or of Krebs cycle, or the systems of protein synthesis. These pathways probably go back to the beginnings of life.

This statement summarizes the fact that all we accomplish depends on chemical reactions and that these depend entirely on the enzymes, ribozymes, and coenzymes we possess. There are innumerable proofs of this.

Take a substance such as vitamin PP (pellagra preventing), or nicotinamide. It is a very simple, small molecule, which must have appeared very early in the history of life, as it is a key constituent of two central coenzymes, called NAD and NADP by biochemists, present in the near-totality of living beings, where they play an essential role in many metabolic reactions. In the course of evolution, one of our distant ancestors lost an enzyme required for the synthesis of this substance, bequeathing this defect to us. This is the reason why we must find nicotinamide in our food. Such is the case for all vitamins.
Otherwise, they wouldn't be vitamins. For some, the loss of a critical enzyme is relatively recent. Thus, primates (to which we belong) and guinea-pigs are the only animals subject to scurvy, the illness caused by a deficiency in vitamin C. All other animals manufacture their own vitamin C. It is told that long-distance voyagers suffering from scurvy because of lack of fresh food recovered from the illness when they were reduced to eating the ship's rats.

The loss of an important enzyme may even be more recent. Many congenital diseases are due to the genetic deficiency of an enzyme and were called “inborn errors of metabolism” by Sir Archibald Garrod, the English pediatrician who first discovered such a condition. Those diseases most often affect a small number of families. Therefore, the mutations responsible for them must have happened in almost contemporary individuals. Tay-Sachs disease, for example, which is restricted to certain Jewish populations, is due to a mutation that has been traced back to the Middle Ages in a small central European village.

Before losing enzymes, living beings must first have acquired them. Life obviously did not arise with a full set of thousands of specific biocatalysts. This would have required instantaneous creation.

The history of metabolism coincides with that of the biocatalysts and can only have been progressive. Sticking to protein enzymes, which catalyze the vast majority of metabolic reactions, molecular studies have allowed two important evolutionary mechanisms to be recognized.

First there is gene
duplication,
with both copies being retained in the genome. This phenomenon allows evolution to “tinker”—the imaginative wording coined by the French biologist François Jacob—with one copy of the gene, eventually making something new out of it, while conserving the other copy unchanged to keep its function going. Numerous examples of this fundamental mechanism are known.

Another important mechanism is
modular combination.
It has been found that many proteins—and, therefore, the corresponding genes—are composed of a number of distinct blocks endowed with special functions, such as a given catalytic activity or the ability to bind a certain substance, a coenzyme, for example. The same blocks are found, often diversely associated, in different protein molecules, suggesting that these are the products of a combinatorial game involving a limited number of modules.

The existence of those modules throws an interesting light on the beginnings of proteins, by suggesting that these substances started in the form of very short chains. This suggestion agrees with theoretical studies that lead, by a totally independent argument, to the conclusion that the first genes must have been very short. It is conceivable that the first enzymes were present among the translation products of those genes, displaying catalytic functions that were no doubt rudimentary, but sufficient to play a role in nascent metabolism. Time, mutations, duplications, tinkering, modular combinations, and natural selection (see
chapter 7
) have done the rest, finally creating the network of mind-boggling complexity, consisting of thousands of highly sophisticated catalysts, that underlies today's metabolism.

But this is not all. Before proteins, as we saw in
chapter 2
, there were RNAs, which are credited with the “invention” of
proteins. Hence the hypothesis, proposed more than twenty years ago, that the stage that preceded metabolism catalyzed by protein enzymes was activated by ribozymes. This notion has been enormously successful, under the appellation of “RNA world,” a hypothetical stage in the origin of life, in which RNA molecules are taken to have played the role of catalysts of the first metabolic reactions and, at the same time, also the role of replicable repository of genetic information (RNA, as we have seen, also preceded DNA).

Without entering into the enormous array of discussions and experiments engendered by this model, I simply wish to underline that it fails to explain certain fundamental questions, including, most important, the origin of RNA itself, the Holy Grail of research on the origin of life (
chapter 2
). It is my opinion, in agreement with that of a number of investigators, but against that of the most enthusiastic defenders of a “pure” RNA world, that a complex chemical infrastructure must have been required to inaugurate this stage in the development of life and to sustain it during all the time it took RNA molecules to generate the first proteins able to assist them by their catalytic activities. This “protometabolism,” as I call it, could already have included certain key reactions of present-day metabolism, issued from protometabolism in congruent fashion. This view is not shared by a number of experts, who believe that prebiotic chemistry was very different from biochemistry.

As to the indispensable catalysts required by protometabolism, suggestions are that they could have been minerals, such as clays; or organic compounds such as peptides, substances similar to proteins, but that could readily have formed under prebiotic conditions; or, again, self-supporting autocatalytic circuits, that is, chemical circuits that generate their
own catalysts. For my part, I lean in favor of peptides, to which I add analogous substances, under the common appellation of “multimers.” Some key coenzymes could already have participated as well in this protometabolism.

The stage at which ATP and its homologues, GTP, CTP, and UTP, first arose raises an intriguing problem. We have seen that these compounds play a dual role of key importance in present-day life: in energy transfer and, as precursors of RNA, in information transfer. The question is: Which of these two functions did the compounds serve first, and how? An implicit feature of the RNA world hypothesis is that information came first (with RNA). My own view is that the building blocks of RNA, that is, the NTPs, must have come first, perhaps inaugurated by ATP, thus accounting for the central role of this compound in metabolism throughout the living world. Supporting this contention is the fact, admittedly only negative, that no pathway to RNA circumventing the NTPs has been discovered or, even, imagined so far. This key question has not yet been subjected to an experimental test that could either confirm or disprove one or the other hypothesis. Time will tell.

R
eproduction is a fundamental property of life, the driving force of life's continuity, generation after generation, from the time of its first appearance up to present-day living beings.

A fundamental property of molecular replication is that it does not rely on direct copying, as in an office copier, but on
complementarity,
as in photography, with a negative serving to assemble a positive, and vice versa. This key mechanism, which was most likely inaugurated by RNA in the origin of life, was discovered first for RNA's better known sister molecule, DNA, by the American James D. Watson and an Englishman, the late Francis Crick, who, in 1953 published their historic paper describing the double-helical structure of the DNA molecule, perhaps the greatest discovery ever made in the life sciences.

The novel notion in this historic proposal was not
so much the helical shape of the DNA molecule, which is imposed by the angles of the chemical bonds and had been suspected before, but rather the molecule's
double
character and, especially, the physical basis of this duality. DNA consists of two strands, twisted together like the threads of a string or, as a more appropriate image, the two sides of a spiral staircase (
fig. 5.1
). Each of these strands consists of a continuous thread, which is the same for all DNA molecules and is made of alternating molecules of phosphate and of the sugar deoxyribose (hence the name of
deoxy
ribonucleic acid, or
D
NA). To this thread are attached, like flaglets to a string, small, nitrogenous molecules, called bases, belonging to four different kinds, which we shall represent simply by their initials: A, G, C, and T. As already seen in the first chapter, the sequence of bases specifies the information content of the molecule, a veritable molecular “word” written with an “alphabet” of four “letters.”

In the DNA double helix, the two strands are complementary according to a very simple rule, called
base pairing:
A in one strand always faces a T in the other strand, and G in one strand always faces a C in the other strand. This means that, with the sequence on one strand known, the other can be inferred. As a simple example, sequence GCCTAT on one strand automatically requires CGGATA on the other. This fundamental property is ensured by the molecular structures of the complementary bases, which have the shape of small flat pieces that fit into each other like two pieces of a puzzle and “stick” together by weak chemical bonds called hydrogen bridges. In the double helix, the base pairs thus formed follow each other like the steps of a spiral staircase, with the threads to which they are attached making the outer frame of the staircase (see
fig. 5.1
). Structures formed in this way may contain thousands, if not millions, of base pairs and reach lengths of
an inch or more. They make up the genome, which consists of thousands of units called genes, each of which contains at least several hundred base pairs.

Fig. 5.1.
The double helix.
Left, schematic model, as it appeared in James D. Watson and Francis Crick's original 1953 paper. The spiral-staircase structure is clearly visible. Right, space-filling molecular model constructed by Maurice Wilkins, who shared the 1962 Nobel Prize in medicine with Watson and Crick. Left, Reprinted by permission from Macmillan Publishers, Ltd. Right, Courtesy of Maurice Wilkins.