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Darwin, Pasteur and the Andromeda Strain

Recombinant DNA research has led to extensive public discussions of two potential risks: the immediate risk of harm from some of the novel organisms produced, and the more conjectural, long-term risk that our interference with evolution will eventually create unforeseeable disasters. These discussions have been based largely on the assumption that any novel organism produced by this technique may well survive and spread. But this assumption ignores Darwin's great discovery: the dominating role of natural selection in determining what survive, multiplies, and evolves. While Darwin dealt only with the visible living world, Pasteur made essentially the same discovery for invisible organisms, though expressed in different terms: bacteria do not arise by spontaneous generation but are ubiquitous, and the kinds that grow out in any medium are the ones that are selected by that medium. An extension of these principles to infectious disease gave rise to the science of epidemiology, which may be viewed as a branch of microbial ecology concerned particularly with the distribution of pathogenic organisms.

I believe that epidemiology and evolution have been grossly underrepresented in the professional as well as in the public discussions of the problem. My credentials for correcting this defect are modest, for my research shifted away from medical microbiology a good many years ago, and since then my contact with the field has depended mostly on textbook writing. But I hope the information I offer will encourage deeper exploration of these topics by experts in future symposia.

To be sure, the most reliable basis for assessing the hazards will ultimately be provided by the accumulation of experience with recombinants. But meanwhile we should not act as though we are entering this new territory with no knowledge to guide us: we have a good deal of pertinent information from evolution and from epidemiology. To molecular biologists who have seen one deep mystery after another in other areas of biology settled by the extremely hard data that their field provides, the evolutionary considerations that I shall invoke may seem like mere hand-waving. But in this light nearly all of Darwin's arguments, based on inferences about the past and not on verifiable experiments, could be similarly dismissed. And I would remind you that Darwin's theory remains the most profound and unifying generalization in biology: it is enormously supported today by the evidence from DNA sequences for the genetic origin and the continuity of the observed variation, but it also involves ecological processes and populational kinetics that require a totally different set of concepts and approaches from those of molecular genetics.

Let us now review some of the pertinent principles from evolution and microbiology.

I. BACKGROUND

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A. Microbiological and Evolutionary Principles

(1) The Meaning of Species. As evolution created the process of sexual reproduction, whose reassortment of genes provides a vastly increased supply of genetic diversity for the mill of natural selection, it also developed species: groups of organisms that reproduce only by mating with other members of the same group, and not with members of other species. The evolutionary function of these fertility barriers is clear: diversity is necessary for evolution, but since a successful organism must have a reasonably balanced set of genes the diversity resulting from unlimited combinations from the pool of genetic material in the living world would not be useful. Species barriers eliminate the production of grossly unfit, non-viable progeny.

Unlike eukaryotes, prokaryotes ordinarily reproduce by the asexual process of cell division. Their occasional gene transfers do not show a sharp species boundary: the transfer simply becomes less efficient the greater the evolutionary separation between the donor and the recipient. Prokaryotes therefore have no true species: they have an almost continuous spectrum of genetic patterns, and the borders between what we call bacterial species are arbitrary and often controversial. E. coli, for example, is the name given to a range of strains with certain common features but also with a variety of differences, and these differences determine their relative Darwinian fitness for various environments. This elementary concept was entirely missing from Cavaliere's discussion of the hazards of inserting genes in E. coli in the New York Times Sunday Magazine last August, and I would criticize the Times for publishing such a polemical and unqualified account.

(2) Bacterial Ecology. Every living species is adapted to a given range of habitats. The set of bacterial strains called E. coli thrive only in the vertebrate gut, and because these cells die out rather quickly in water the E. coli count of a pond or a well is a reliable index of its continuing fecal contamination. In the gut there is intense Darwinian competition between strains, depending on such variables as growth rate, growth requirements, ability to scavenge traces of food, adherence to the gut linings and resistance to antimicrobial factors in the host. Hence most novel strains are quickly extinguished. The mechanism of this extinction is the kind of selection by competition envisaged by Darwin for higher organisms, but with bacteria it happens in days rather than in eons.

This effect of the environment in the gut on the normal flora is readily recognized. For example, when breast feeding is replaced by solid food the character of the stool changes dramatically, as lactic acid bacteria (which produce sweet-smelling products) are replaced by E. coli and other foul organisms. Early in this century Mechnikov romantically hoped to promote longevity by supplying lactic acid bacteria, in the form of yogurt, to displace the presumably toxic foul organisms. The experiments were a dismal failure, but the commerical success is still seen.

(3) Pathogenesis. Only an incredibly small fraction of all bacterial species can cause disease. The rest play essential roles in the cycle of nature. Infectious bacteria differ from each other in several distinct respects: infectivity (i.e., the infectious does, ranging from a few cells of the tularemia bacillus to around 10-6 of the cholera vibrio); specific distribution in the body; virulence (i.e., the severity of the disease produced); and communicability from one individual host to another. These attributes depend on the coordinate activity of many genes, which are capable of independent variation. For our discussion the distinction between the ability to produce a serious disease and the ability to spread is particularly important.

(4) Types of natural selection. When an organism grows continuously in a relatively constant environment natural selection has a stabilizing effect, weeding out the variants that deviate too far in any direction from the well adapted norm. But when the environment is changed the same basic process of natural selection has a diversifying effect: the new circumstances select for the preferential survival and reproduction of variants with increased fitness for those circumstances. This Darwinian process explains a phenomenon that confused early workers: when pathogenic bacterial strains are isolated from infected hosts and then repeatedly transferred in artificial culture media they often rapidly lose virulence. We now know the mechanism by which this improved adaptation to the new environment occurs, at the expense of decreased adaptation to the old one (i.e., loss of virulence): the original strain is gradually outgrown by the progeny of are mutants that are better adapted to the new culture medium (i.e., that can grow slightly faster, or can grow slightly longer with a limited food supply).

It is clear that natural selection plays an overwhelming role in evolution, though with bacteria its role was long unrecognized: the population shifts seemed too rapid for an undirected process, and the existence of genes and mutations in bacteria was not recognized until the 1940s. But by now selection has become the foundation of bacterial ecology.

II.HAZARDS

In trying to estimate the immediate hazards from novel organisms it is useful to distinguish three possibilities: that experiments with a given kind of DNA will produce a dangerous organism; that the organism will infect a laboratory worker; and that the organism will spread.

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