Future Studies Of Pathogens Depend On Conserving Microbes

The conservation of biodiversity is a universally applauded good, bringing to mind the aesthetic values of elegant felines and brilliantly plumaged birds. The rain forest and other plants have also been the source of many important pharmaceuticals, which can be assessed for their economic and health-giving powers. We need but mention familiar examples like quinine and aspirin (and we cannot ignore morphine and cocaine-albeit opium poppies and coca bushes are in no danger of extinction). We should then, the argument goes, make additional investments in preserving the rain forest to have the opportunity of further pharmaceutical discovery. I strongly support the conclusions, but warn that this reasoning is far too narrow. Illustration: John Overmyer To begin with, the premise would open the door to triage founded entirely on economic value. Once some plant species had been investigated-and most of them will be devoid of pharmacological activity-then these would be candidates for discard. Rather than focus on specific drug products, we should look on every plant as an exemplar of a metabolic web, with systems of biochemical synthesis that are an inexhaustible treasure trove of learning. The phytochemistry of higher plants is but the tip of the iceberg. Under the surface is the microbial world, which has given us the lion's share of new drugs-mainly antibiotics for bacterial infections, but important anti-cancer and other drugs as well. So I am going to position myself as an advocate for the microbial world, which is hardly mentioned by conservationists. It is usually assumed that the bugs (not Hemiptera, but bacteria and the like) can take care of themselves. Truly, bacteria and viruses are our only contenders at the summit of the food chain, and the competition is often a deadly one. Nor can it be taken for granted that the outcome will always favor the larger species. It is amazing that microbial infection is not thought of more often in discussions of faunal extinctions, and it was scarcely mentioned by Darwin as a factor in natural selection. We certainly know of many plant and some animal species that have been devastated if not extinguished by their encounter with microbes: in the New World, Native Americans and the indigenous chestnut; most recently the seal populations almost everywhere; and the lions in Serengeti. Most conservation is directed to species that promise some overt benefit, be it aesthetic or material, or at worst have a neutral impact on human welfare. Marginal exceptions may include carnivorous predators, even great white sharks. The main burden of the "Jurassic Park" scenario may be this: Were velociraptors to be revived, they would be declared endangered species and offered the full protection of the law. Contrary to the ethos of preserving biodiversity, we do then expend great effort on the eradication of parasites and vectors, which exact an enormous toll on human health and viability. I am loath to shed a tear for the fate of vectors of river blindness, malaria, or trypanosomal infections, or for the parasites themselves. Nor does it appear likely that the eradication campaigns for all of these will succeed in the near future. Further, the arthropods and worms are not easily maintained, even in the laboratory-and there is no question of a natural, and uncontainable, habitat for them. But these paradoxes will have to be dealt with in due course, and we will face the reality that we have far from exhausted the scientific and biomedical knowledge that can be gleaned about pathogenic processes. The policy and operational issues bearing on conservation are quite different for microbes, in some part because they are by far the least well cataloged of living organisms. We don't have much insight into the scarcity of habitats for microorganisms, which occupy such a diversity of niches, and which we generally do not think about in terms of geographic restrictions. At the very minimum, we should recall how many species have specific parasitic, symbiotic, and commensal associations with particular plant and animal species. A huge bacterium, almost a full millimeter in length, was recently described as a symbiont in surgeonfish. Like the vast majority of microbial species, this has not been cultivated. The basic taxonomy of the biological world has just been revised, with the now generally accepted authentication of a new kingdom, the Archaea, from the wonderful and iconoclastic work of Carl Woese at the University of Illinois. These bugs tend to live in strange habitats-extremes of temperature, pH, and pressure. We have no idea about how many there are or the prospects of endangerment. They will surely give us technological enhancements, even beyond the thermotolerant eubacterium Thermus aquaticus, which is at the seat of practical polymerase chain reaction DNA amplification, and the host of subsequent applications. The main point is the recency of these phylogenetic insights, and the broad array of data we will need to understand our roots in biological evolution. For the microbial world, biodiversity is importantly preserved in culture collections, collective assets for which it is often difficult to sustain the needed material support-as applies also to germ plasm banks for plant (and perhaps animal) varieties. New technologies of preservation are in the offing; and eventually the reduction of biological identity to DNA codes will carry us a long way. But among the losses incidental to macrobiotic species will be their associated microflora. It is hard to emphasize sufficiently the converse: how crucial microbial symbionts are to survival of many plant and animal species-briefly noted, symbiotic nitrogen fixation for legumes, complex rhizospheres for most tropical plants, the light organs of deep marine animals, the zoochlorellae of innumerable marine invertebrates, and the mycetomes of insects. Lynn Margulis at the University of Massachusetts, Amherst, and Jan Sapp at York University in Toronto have given us lyrical accounts of the new pattern of non-Darwinian evolution, evolution by association, betrayed by these examples. Natural products from plants have certainly inspired the imagination of organic chemists in ways that even the new compounds found using combinatorial chemistry (K.S. Brown, The Scientist, May 13, 1966, page 1) may have trouble matching. Nevertheless, most of the phytopharmaceuticals in modern times are among the antibiotics, and these are of bacterial and fungal origin. Hundreds of thousands, if not millions, of isolates have been screened. The issue of conservation is seen less in regard to their natural habitats, poorly understood as they are, but more in regard to what has happened to most of those isolates. Worse than having been merely discarded, many of them are burdened with expired patent claims, deflating the incentives to revive them for newfound uses in an era when we complain of having run out of antibiotic innovations. So we have another set of endangered species, crying out for more imaginative policies to encourage their rehabilitation from the abandoned archives. Paradoxically, little imagination has been spent (or it just has not succeeded) on trying to understand what these complex phytochemicals are doing for their host species. It is far from clear that antibiotics actually function as such in the soil. And how dysfunctional it is for the Pacific yew to be a source of taxol, an anti-cancer drug. One research approach would be to tease out the evolution of the anabolic pathways for these substances, down to the level of the DNA homologies of the component enzymes. We should be able to do a bit better than the technology of the past century, random screening of plant extracts for biological activity. The natural history of the pathogens themselves is at the core of therapeutically oriented research. It has been of the utmost importance to collect all possible strains of pneumococci or Shigella or Salmonella or smallpox or flu, for the tracing of epidemics and the construction of vaccines and trials of antibiotics. With the rampant emergence of antibiotic resistance, it has become even more important to understand the diffusion of these mutant genes via plasmid transfer, from one species to another, even across kingdoms. Plasmid transfer then underlies a worldwide web of promiscuous exchange of genetic information. These studies based on natural history have led to the most important advances in biomedical science in this century: the diversity and transformation of pneumococcal serotypes and the ensuing discovery in 1944 that DNA is the genetic molecule. Should we contemplate extirpating pathogenic microbes, not merely as hazards of naturally communicated infection, but as objects of continued laboratory study? We are fortunate that this is an option, but so far in just one example, consequent on global vaccination and the elimination of smallpox as a naturally communicated disease. It is easy to understand the motives of the public health workers, many of whom have contributed heroically to this outstanding achievement, that they should now seek the destruction of laboratory stocks. Photo: Lynn Gambale Joshua Lederberg is Raymond and Beverly Sackler Foundation Scholar at Rockefeller University. This article is adapted from a presentation to a symposium on biodiversity and human health at the Smithsonian Institution, April 4, 1995. There is then a current controversy, seated largely at the World Health Organization, about proceeding to the final implementation: a bug-burning ceremony that would enable us to stop having to think about smallpox forever. (No legal structure is in place to ensure uniform global compliance with such a directive.) The main fuel for these arguments is concern about the hazards of escape of live virus from its repositories. On the other hand, variola is by no means the most dangerous of hazards among viruses currently studied, and we are hardly sure that the virus does not still survive in cemeteries in the frozen Arctic (W.K. Joklik, The Scientist, Dec. 9, 1996, page 11). This is being actively studied by Lev Sandakhchiev and his colleagues in Novosibirsk, in connection with oil and gas exploration in those territories. The enterprise is one in which other countries would wish to be active partners. The remarkable host specificity of this virus is but one of many biological questions that are potentially answerable in future. I would add the prospects of chemotherapy and of pathogenesis mitigation, as we begin to understand how such viruses recruit the host's cytokines. But not, of course, if the remaining laboratory stocks are destroyed as currently planned. We are just beginning to develop the most exciting and potent tools for enquiry-like transgenic tissue culture cells and animals-for exploring such matters; but the destruction would be an irrevocable step. If it were held in limbo, we could return to it from time to time with new technological insights and know better the tradeoff of potential values. Meanwhile, we could elaborate an appropriate international regime for participation in safety oversight, and in eventual experimentation, allay any allegations that the superpowers are claiming a monopoly on this medical-scientific target.

Future Studies Of Pathogens Depend On Conserving Microbes

Interested in reading more?

Become a Member of