Mon Jan 17 14:35:22 EST 2000

In the history of human encounter with infectious disease, the current millenium’s defining
year is better lodged at about 1877, than at an arbitrary 000 C.E. That year saw the
consolidation of the germ theory of disease, through the researches on anthrax by Louis
Pasteur and Robert Koch. It was soon followed by effective veterinary vaccines for anthrax,
and then the systematic search for every other disease-causing microbe: the golden age of
microbiology had begun. It was soon enriched by the discovery of filtrable viruses, particles
too small to be seen with the conventional microscope, or to be cultivated on artificial media.
There had been many anticipations of germs: Fracastoro had sung in 1546 of "seminaria"
(seeds) to account for the spread of the "French Disease” (syphilis). The terrified targets of
the Black Death in Europe after 1346 had some intimation of contagion though distracted by
scapegoatery of witches and Jews. Edward Jenner had developed vaccination for smallpox in
1798, by purely empirical routes and little or no insight into its mechanisms (a cross-reacting
virus variant and the host’s immunological response). Leeuwenhoek, in 1684, with his simple
new microscope, had visualized bacteria among the animalcules seen in scrapings from his
teeth. On the therapeutic side, Jesuit missionaries in Peru had noted the native Indians’ use
of Cinchona bark, and brought this to Europe in 1637 for the treatment of malaria. This
quinine was one of the small handful of medications available to physicians prior to 1877 that
actually worked any benefit. (We can think of a few other botanicals: opium, digitalis,
willow bark [salicylates], but none for infection.)

These scattered landmarks appear in sharp contrast to the ever growing tidal advance of
scientific enquiry that succeeded the pioneers of 1877: the institutionalization of microbe
hunting and of the systematic enjoyment of scientific analysis of disease processes and of the
microbial world. Sanitary reform had not waited for these scientific advances -- mounted in
revulsion at the squalor and the stinks of the urban slums that followed upon the industrial
revolution in England and the U.S. Although flawed in detail, the hygienic movement that
tried to scrub up dirt and sewer smells did have some health impact in mid 19th century,
though it failed when fleas, mosquitoes and sewage leakage into water supplies were ignored.

As witness to the millenial ascent, vital statistics were also diligently recorded after 1900 for
the U.S. as intelligence for the quest for new knowledge and its application to the struggle for
public health. The U.S. experience is graphically displayed in (Fig. 1) depicting life- ,
expectancy at birth through the century. Similar trends applied to most other industrialized
countries, with lags and disparities for economically and socially depressed sectors. The
outstanding message is the near doubling of lifespan from 47 years in 1900 to 77 at present.
(Count 74 for males, 80 for females -- a gap partly explained by the female double-X-
chromosome’s buffering against accumulated recessive mutations, and illustrated by male-
prevalence of conditions like color-blindness and hemophilia.) As shown in Fig. 2, the
decline in mortality ascribable to infectious disease accounted for almost all of the
improvement up to 1950, when life expectancy had reached 68. Besides the major improving
trends, we also observe the jaggedness, the year-to-year fluctuations in the graphs 1900-1950,
again attributable to sporadic outbreaks of particular infections (typhoid fever, tuberculosis,
scarlet fever) which no longer loom large in numerical statistics. Outstanding is the spike of
1918, the great influenza pandemic, to which we shall return.
Further improvement is on an asymptotic limb, and it has taken the second half-century to
gain another decade of lifespan. Crude mortality rates have not altered very much, but we
must give credit to the more advanced age of the population at risk. Heart disease has been
the looming threat, accompanying affluence along with senescence. Eventually we accrue
benefits from permeation of more salutogenic life styles (regard for diet, smoking, exercise;
tacit medications like aspirin) bolstered by specific medical and surgical interventions.

The earlier advances rest in part on childhood immunization and other science-based medical
interventions, but at least in equal measure on public health measures: protection of food and
water supplies, segregation of the coughing patients; personal hygiene. Overall economic
growth facilitated less crowded housing, improved working conditions and leave for stressful
illness, and better nutrition, which have all played a role in setting a baseline of health
expectations. Then in the 1950’s we had an array of wonder drugs -- the new antibiotics:
penicillin, streptomycin; chloramphenicol, and a growing list which promised to put an end to
bacterial infectious disease. For viruses, we had (and have) far fewer remedies, but an array
of new vaccines offered prophylaxis -- polio and the names of Jonas Salk and Albert Sabin
the most indelibly inscribed on the public mind. Old vaccines like Jenner’s cowpox were also
mobilized in great campaigns, leading to the eradication of smallpox as an extant human
disease by the end-70’s.

Little wonder that by the mid 1960’s, we heard a common exclamation that infection was past
history; the microbes had been conquered; we should turn our attention to the constitutional
scourges of heart disease, cancer and psychiatric disorder. This triumphalism was echoed in
the priorities for research funding and of pharmaceutical development, e.g. as expressed in the
national crusade against cancer, initiated by President Nixon in 1971 with some implied
promise that cancer would also be conquered by the bicentennial celebrations of 1976. If
anyone believed that then, we have come to understand that new conquests would be a long
haul. The isolation, cultivation and analysis of microbes are far easier tasks than studies on
humans. Studies on constitutional disorders are fraught with the material and ethical taxes
levied on work on the human body. Agents that will selectively recognize and kill parasites
are easier to design and test than those that must discriminate between normal versus
abnormal human cells.

Although they had been for a time dethroned as objects of health-phobia, microbes
nevertheless became and remain popular investigative objects for the most basic studies in
molecular physiology and genetics. During the acme of microbe-hunting, say 1880 to 1940,
bacteriology was almost totally divorced from general biological study. Pasteur and Koch are
scarcely mentioned by the founders of cell biology and genetics like E. B. Wilson and T. H.
Morgan. Bacteriology was taught as a specialty in medicine, outside the schools of basic
zoology and botany; bacteriologists scarcely heard of the conceptual revolutions in genetic
and evolutionary theory. Prior to the electron microscope, the bacterium’s internal structure
was elusive -- and lacking an organized nucleus would only be confusing. Most biologists
when they mentioned bacteria at all regarded them as mysteriously pre-cellular: it was an
audacious leap for Rene Dubos to entitle his 1945 monograph "The Bacterial Cell".

This segregation of instruction and thought disinformed researchers about the prospects of
conducting genetic investigation with bacteria. So it is paradoxical that the pivotal discovery
of molecular genetics, that genetic information resides in the chemical sequence of DNA,
arose from studies on serological types of the pneumococcus, important in tracking epidemics
of pneumonia. Fred Griffith, in London, had reported in 1928 that serotypes could be
interconverted with extracts of specific cell types. Oswald Avery followed up this work at the
Rockefeller Institute in New York, and with Colin MacLeod and Maclyn McCarty reported in
1944 that the active substance was DNA. They and others spent much labor at further proof
to exclude contaminating protein as the vehicle of biological activity. Those findings ignited
a renewed interest in what was really going on in the life cycle of bacteria, and led
immediately to my own work (1946) on sexual conjugation in Escherichia coli and the
construction of chromosome maps closely emulating what had been going on in the genetics
of fruitflies, maize and mice for the previous 45 years. Bacteria and bacterial viruses
remained the initial testbed for most of the subsequent development of molecular genetics,
and the consequent biotechnology, despite a waning interest in these microbes as etiologic
agents of disease.

That complacency was shattered by the emerging recognition of AIDS starting in 1981. The
chronically spreading pandemic has overtaken one continent after another, at terrible cost, and
rapidly disillusioned our confidence about mastery over the microbes. It is coincident with
the looming breakdown of efficacy of antibiotics as the evolutionary process takes hold in the
microbial world, its counterattack with the emergence of resistance. HIV, the AIDS-virus,
falls in the category of retroviruses, which had also been laboratory curiosities since the initial
discovery of the (Peyton) Rous Sarcoma Virus in 1911. Serendipitously, the RSV had been
under intensive study for years as a model for cancer, and the interchange of oncogenes by a
viral vector. This greatly accelerated the characterization of HIV as a retrovirus, and assisted
our first feeble steps at generating medications that mitigate the pace of HIV infection. This
simplest of viruses still frustrates the most concentrated regime of focussed biomedical
research ever mobilized. Perhaps our zeal to extirpate the virus has clouded less ambitious
aims of learning to live with it, through nurturing the immune system eventually eroded by
HIV in the human. Natural history points to analogous infections in simians that have long
since evolved to a mutually tolerable equilibrium.

This costly experience has provoked widespread re-examination of the terms of our
cohabitation of the planet. With more enthusiastic monitoring came a realization of an
unbroken stream of outbreaks of exotic diseases: some new imports, some the belated
recognition of older parasites, some newly evolved organisms (Fig. 3). Cholera (in the
Southern Hemisphere), Legionella, antibiotic resistant pneumonias would be typical examples,
respectively. New roles for infectious agents were revealed from closer study of gastric ulcer
and the revelation of a Helicobacter for a disease that had been attributed almost entirely to
psychosomatics. In like fashion, stress is now competing for etiological attention with
Chlamydia infection as a cause of atherosclerosis and coronary disease. Four million
Americans are now estimated to have been infected with Hepatitis C (mainly by transfusion
or other contaminated blood products). This population is at significant risk of liver cancer,
and must be warned to avoid hepatotoxins like alcohol -- as well as to be cautioned about
donating blood. Smaller, but lethal outbreaks of Ebola virus in Africa, and hantavirus with
pulmonary syndrome in the Southwest U.S. attracted popular attention disproportionate to
their immediate public health significance, but not to their potential if they were to mutate to
more diffusible forms, or other ecological factors favor their spread. We had to reconsider
the likelihood of a recurrence of a lethal influenza, like the "Spanish flu" of 1918, which had
killed at least 20 million people worldwide, a match for the belligerent casualties of World
War I. The genetic processes of gene reassortment in flu viruses, poorly confined to their
canonical hosts -- birds, swine and people -- go on relentlessly and are surely bound to re-
generate human-lethal variants. Those thoughts were very much in mind during the
progression of an avian flu, H5N1, into a score of Hong Kong citizens during 1997 - with a
third of the cases lethal. We have no idea why only these few humans succumbed; but we
certainly owe a great debt of gratitude to the Hong Kong health authorities for their resolute
actions, including the immolation of 2 million chickens, which in the event did stem that
outbreak and avert the possibility of a worldwide spread of HSN1 -- though wildfowl may yet
have the last word. We had a similar scare in New York with the unprecedented appearance
of bird- and mosquito-borne West Nile Encephalitis, though happily with a very low mortality
ratio. Will we see it again next Spring? On a much larger scale, Malaysia was afflicted with
a new entity, the Nipah virus, with up to a hundred human fatalities, and a million livestock
to be sacrificed.

In more quantitative terms, the US mortality index (annual deaths per 100,000) attributable to
infection crept up from about 30 in 1982 to 60 in 1994. It had been steady for the prior 30
years. In relative terms, the rekindling is still modest compared to the 500 of the year 1900,
or 850 at the 1918 spike. About half the recent uptick matches the AIDS pandemic; for the
rest, respiratory disease, antibiotic resistance, and nosocomial infection play a significant role.

We may turn now from a historical to a contemporary and future-oriented one.

What are the zones of risk? What precautions can and should we be taking? Are we more or
less vulnerable today than 20 or 50 years ago? Can we get a deeper understanding of the
roots and origins of pathogenesis, and how can this inform our strategies?

The instabilities of cohabitation arise from two main sources, loosely definable as ecological
and evolutionary.

Ecological comprises the ways in which we alter the physical and biological environment,
microbial, animal and our own habitats, and our intersections with the parasites’ modus
vivendi. These includes all of hygienic and therapeutic interventions, "Our wits versus their
genes", which have gained us added longevity and softened the pall of infant mortality --
thereby irrevocably changing our own human ecology. As side effect, together with economic
(especially agricultural) productivity these have been the substratum of the population
explosion. That spread is also the main source of new vulnerability: crowding of humans,
with slums cheek by jow] with the jetsetters’ residences; incursions into the forests for
agriculture or suburbiana, with closer contact with rodents and ticks; unmitigated travel. It is
a new historic experience that round-the-world travel is consummated in less than 80 hours
(much less than the 80 days of Jules Verne’s fantasy.) And this has become an everyday
experience: well over a million passengers board aircraft every day for international
destinations. International commerce by ground, sea and air -- for example in foodstuffs --
does but add to the traffic of potential pathogens and vectors. The transit times are short
compared to the incubation times of disease, reducing health quarantine to a near absurdity.
Our systems for monitoring and diagnosis of exotic disease have nowhere nearly kept pace
with this qualitative transformation of global human and material exchange. In contrast to
1918, a new flu could transit the world and pop up simultaneously in a dozen new locations
with limited hope of even identifying the primary focus of this metastasis. This cauldron will
then redistribute people, their culture, their prior immunities, their inherited predispositions,
with pathogens that may have been quiescent at other locales for centuries. The most evident
precedent is the European conquest of America, attended - even enabled - by pandemics of
smallpox and measles; and the payback to Europe of syphilis’ Treponema.

New technology is part of the ecological armamentarium which may go a long way to
reinforcing our defenses; and it may be said that this obligation is beginning to be understood
by high national policy. It should also bolster our commitment to international organizations
like WHO for global health improvement. AIDS in America and Europe may be regarded as
penance for near obliviousness to the frightful health conditions in Africa, which remain far
behind the celebration of millenial ascent depicted in Fig. 1. At least some cutting-edge
internet communications technology has been harnessed for prompt global alerts of emerging
diseases: see http://osi.oracle.com:8080/promed/.

On the evolutionary side, we may ponder intrinsic changes in genotype, both in the human
host and in the world of germs. Charles Darwin was well aware of Pasteur and Koch’s
contributions, and optimistic about their contribution to human welfare. Koch’s mentor,
Ferdinand Cohn, was a frequent guest in Darwin’s home. It is the more remarkable then that
infection is all but totally ignored as a factor of natural selection in Darwin’s writings. For
my own discussion, I must concede how difficult it is to corroborate an evolutionary
narrative, and we must regard this one as a provocation to experiment rather than a settled
account. Darwin, had he been so inclined, was not yet able to recite a concrete example of
hereditary adaptation to disease. This had to await J.B.S. Haldane’s speculation in 1949 that
the prevalence of hemoglobin disorders in Mediterranean peoples might be a defense against
malaria. This did precede, if not necessarily inspire, A. C. Allison’s report of the protective
effect of heterozygous hemoglobinopathy against falciparum malaria in Africa. The side
effects of this bit of genetic engineering on Nature’s part are well-known: the heavy burden of
sickle cell disease when this polymorphism is driven to higher gene frequencies, and the
morbid homozygotes become more prevalent. Since then, a handful of similar examples have
been deciphered, the majority connected with malaria. Why so? Malaria and tuberculosis are
the two scourges so prevalent that ameliorative predispositions will be both strongly selected
and obvious for ascertainment. In a similar vein, we have news that a ccr5 (chemokine
receptor) deletion offers some protection against AIDS,but not yet any clarity as to what may
have driven that polymorphism in earlier human history.

The small lessons to be gleaned are how fitful and sporadic human evolution is when our
genetic change (measured in generations to millenia) is pitted against microbial attack. We
have inherited an adaptive immune system, little changed since its early vertebrate origins 200
million years ago. In its inner workings, immunity is a Darwinian struggle, with randomly
generated diversification of leukocytes to prime their duel with an unpredictable invader. But
this duel is in the soma, with nothing passed on to the host genome to mark a successful
encounter. It is plausible that we might we inherit a predisposition for good immune
responses to the pathogens most prevalent in our racial experience -- but so far this is hardly
tested, even for species comparisons. A uniformitarian ideology about immunity may have
hindered more inspired searches for species-restricted innovations in defense against infection.
By contrast, the germ that wins the battle does proliferate its genes for success, and can use
those enhancements to go on to new hosts, at least in the short run.

"Germs" have long been recognized as living entities. Indeed there is an ambiguity in that
nickname to suggest their affinity with "genes". Viruses, with some realism, were credited
with being "naked genes" long before they joined the repertoire of molecular genetic
investigations, Nevertheless, the idea that they might be evolving has been slow to sink into
the ideology and practice of public health. At our millenial dawn, Robert Koch was obsessed
that rigorous technique would support the doctrine of monomorphism: the invariance of
microbial species in pure culture. Purported "variants" were more likely to be aliens that had
floated into the Petri dishes from the atmosphere. Much the same might be said (and truly)
about many claims of complex morphogenesis and life-cycles among common bacteria.
Koch’s rigor was an essential riposte to careless claims of interconvertibility, e.g. that yeasts
could be converted into spirilli or cocci. Koch himself relented in time, admitting some
possibility of variation, but for him and his contemporaries this was a nuisance rather than the
essence of microbes’ competence. The multitude of isolable species was confusing enough to
the epidemic-tracker; it would be almost to much to bear to cope with new variants of altered
serological specificity, host-affinity, or virulence. Even today it would be near heresy to balk
at the identification of the great plague of the 14th century with today’s Yersinia pestis; but
we cannot readily account for its ready pneumonic transmission without guessing at some
intrinsic adaptation to aerosol conveyance. Exhumations of ancient remains might still
furnish DNA evidence to test such ideas.

The molecular genetics that began in 1944 has changed all that, and microbial systems
provide our most convenient models for experimental evolution. Diverse mechanisms for
genetic variation and recombination are spelled out in ponderous monographs. Assays for
chemical mutagenesis are now routinely exercised on bacteria (the Ames test, with
Salmonella), as testimony for the accessibility of bacterial DNA to environmental insult.
Mutators abound, and may be switched on and off in accord with the variegation of the
ambient scene. The germs are promiscuous, notably in plasmid transfer conferring resistance
to antibiotics, so that innovations are not species-bound. Indeed, the microbial biosphere can
be thought of as a world wide web of informational exchange, DNA transfer as the internet.
That DNA, in the case of many viruses may be integrated into host genomes; then later
remobilized to form active, transmissible particles: hundreds of segments of human DNA
originated as integrated retroviruses from historical encounters. Most important is the
vastness of population size, and the intensity of its fluctuation. Microbial populations may
fluctuate by factors of 10°10 on a daily cycle, as they move between hosts, or as the host
exploits antibiotics or antibodies to defeat them. If we set out to compare the pace of
evolution from a priori argument, it would be conservative to give a 10°6 or 10°9 advantage
to the microbe compared to the multicellular host. A year in the life of bacteria would easily
match the span of mammalian evolution. We ought then be quite fearful of the outcome of
the contest, barring only what we could bring to the contest by way of technical wit and
social intelligence. We would still wonder, how account for the reality that, however
punctuated is our history with catastrophic plague -- and evidence of sporadic species
wipeouts in natural history -- we are indeed still here!
That may be taking a too Manichean view: "us good, them evil". Yes, at the top of the food
chain, the human species shares the summit only with micropredators. We also know our
eventual fate, if not by fire, then our remains will be restored to the geosphere by some form
of microbial combustion. The real contest is between the greedy parasites and the ubiquitous
saprophytes in ensuring the ultimate triumph of entropy. Why are we still here?" In fact the
parasites have a shared interest in our survival: the death of the host is a dead end for every
invader, bar a few bottom-feeders. To domesticate the host is a preferred outcome for the
longer run. This has no more persuasive example than the most successful of all microbes:
the mitochondria. These have invaded every eukaryote (embracing yeast, protozoa, and all
multicellulars), and provide the machinery of oxidative metabolism. Other bacteria have
evolved into the chloroplasts: these are the primary captors of solar energy, emitting both
oxygen and the fixed carbon that nourishes the biosphere. Who has domesticated whom?
Every animal builds its existence around the recapture of that food, including the relentless
burden of heavy breathing to sustain the respiration, to stoke the mitochondrial furnaces.

These ideas have been voiced over many years, sometimes too emphatically as if the parasite
has an active intelligence to guide its symbiotic restraint. In the short run, the infected host is
at metastable equilibrium: think of it as a superorganism, with the respective genomes yoked
in a form of chimera. The host’s immune response may be excessive, with autoimmune
injury (not least from cytokines) a byproduct. On the microbes’ part, as with rogue cancer
cells, exuberant deviant cells may overtake the soma, with their own demise and that of the
parent population the outcome. In a broader reach, it is as important for parasites to moderate
their virulence once established, as it is for them to have aggressive means of entering the
body surfaces and radiating some local toxicity to counter the hosts’ defenses. Lacking to
date has been any systematic study of that optimization. We are so focussed on
hypervirulence as a research paradigm that we neglect the physiology of homeostatic balance
in the infected host qua superorganism.

That the burden of mutualistic adaptation must fall largely on the parasite is a corollary of the
evolutionary pace: at odds with the more popular teachings of co-evolution, where host and
parasite genomes negotiate their coexistence. When a parasite enters another species, what
we then call a zoonosis, the outcomes may be divergent. In many cases, there will be no
infection at all -- we ignore that. In others, the host environment is not greatly altered, and
we may have similar infection, as with many enteritides. Exceptionally, the parasite is
maladapted to the new host, through lack of prior experience, and the restraints fail: we call
that a virulent zoonosis, with such examples as psittacosis, Q-fever, rickettsioses, or
hantavirus. Human infections play a small part in the life cycle of these zoonoses, so that
selection for moderation is inoperative. From this perspective, the ill-adapted pathogen is the
one that has not surveilled the host genome and not parlayed its own genome to optimize its
position on the scale of virulence. Host genomes will also adjust themselves, but on an
incommensurably slower time scale. Almost by definition, most of our experimental models
of infection are zoonoses, alien hosts to simulate human disease. The operational ideal is the
mouse succumbing overnight to inoculation of a few cells. This is superb for "in vivo"
testing of an antibiotic, but bears little relationship to the dynamics of everyday human
disease.

In its dominant role the parasite may go so far as to manipulate the immune system of the
host to its own advantage. I’d suggest that a parasite will tend to display just those epitopes
as will a) moderate but not extinguish the primary infection, and b) will inhibit superinfection
by competing strains, of the same or even of other species. According to this doctrine, the
symptoms of influenza are evolved in part to help ward off other viral infections. This is
purely speculative, but the doctrine does have substantial support in tuberculosis and in
schistosomiasis. The HIV fails in the end when opportunistic infections supervene to kill the
host as a byproduct of the virus’ protracted duel with the host’s cellular immune system. We
need generally to look more closely at earlier stages of chronic infection for cross- protective
factors. Helicobacter has been found to secrete antibacterial peptides that inhibit other
enterics, and HIV and other lentiviral envelopes also do make antimicrobials -- their
significance for natural history of disease as yet unknown.

Parasite dominance may also account for some paradoxes: many of the most successful
pathogens are slow-growing and nutritionally fastidious. Invasive bacteria do not produce the
most potent toxins -- these are left to the clostridia (botulinum, tetanus) which are mainly
carrion-feeders and soil inhabitants, for whom people are the most incidental hosts. We may
think of sexually transmitted disease as incidental to our erotic proclivities. However, it is
not a facetious suggestion that parasites invented sex, e.g. the apparatus of bacterial
conjugation, as their method of moving from one host to another, is today exemplified by
many plasmids which have encoded the transfer apparatus in their own genomes.

Within the past decade, the complete genomes of many microbes have been displayed, but
they are far from unravelled. Most observers have been impressed by their complexity,
diversity and novelty, at the same time as they see evidence for the web of interchange
permeating the evolutionary charts. Innumerable genes have yet to have their functions
explored -- a marvelous opportunity for the definition of therapeutic targets. Together with
wiser insight about the groundrules of pathogenic evolution, we have a platform for new
generations of success in responding to the challenges of infectious disease: certainly many
new vaccines, antibiotics and immune modulators. The lesson of HIV and other emerging
infections has also begun to take hold in government and as a market opportunity for an
invigorated biotechnology industry. If we do the hard work, and take no success for granted,
we may be able to forfend recurrences of 1918 (influenza) and 1981 (HIV) in the further
history of this millenium.

The executive summary of this discussion is a plea for a more ecologically informed research
program in infectious disease, a germ’s eye view, if you like. Besides the morbific colonizers
of our skin, gut and mucous membranes we are host to a poorly catalogued ensemble of
symbionts to which we pay scant attention. Yet they are equally part of the "superorganism"
genome with which we confront the rest of the biosphere. Their protective role is already
attested to by the superinfections that often attend specific antibiotic therapy. Intermicrobial
competition in the soil was recognized for decades before its exploitation by Dubos and
Waksman in seeking the early antibiotics. The microbial ecology of our own bodies is
overdue for yielding similar fruit. Another corollary is a caveat about the eradication of
pathogens (like smallpox, and soon polio) absent a strategy for sustaining some level of
immunity, guarding against a possible recrudescence. This might be achieved by our
domestication of commensals to bear relevant cross-reacting epitopes, or alternatively to
implant these into food additives. At a cruder level, a super-hygienic environment might be
to our disadvantage if we fail to understand what we then lack by way of immunogenic
stimulation. If we dare not return to random filth, biosynthetic dirt may be the recipe.

CODA The moderately optimistic note of the foregoing discussion is premised on the rational
investment in technology and social systems needed to understand infection and moderate its
impact. There is a darker side to that microbiological engineering: its prospective use for
biological warfare (BW). As often remarked, BW may become the poor man’s atomic bomb;
if not now there is the prospect of eventual development of etiological agents and systems to
deliver them that would justify such nightmares. Future technology is likely to favor the
offensive; technical defenses are unlikely to meet all of the threats that can be collected today
or designed tomorrow. As a measure of social intelligence, it would be a positive mark if
there could be a consolidated consensus to internalize and enforce the 1975 BW disarmament
convention. The moral basis of that is a global crusade to enhance and apply scientific
knowledge to counter infectious disease everywhere. =========

Fig. 1 Life expectancy

Fig. 2 Infectious disease mortality

Fig. 3 Table, examples of emerging infections.

Fig. 4 Timeline.

==== Fig. 3 Table, examples of emerging infections.

Examples of pathogenic microbes and infectious diseases recognized since 1973
from CISET report 1995

Year Microbe Type Disease
1973 Rotavirus Virus Major cause of infantile diarrhea
worldwide 1975 Parvovirus B19 Virus Aplastic

crisis in chronic

hemolytic anemia 1976 Cryptosporidium parvum Parasite
Acute and

chronic diarrhea

1977 Ebola virus Virus Ebola hemorrhagic fever
1977 Legionella pneumophila Bacteria Legionnaires’ disease
1977 Hantaan virus Virus Hemorrhagic fever with renal
syndrome (HRFS) 1977 Campylobacter jejuni Bacteria

Enteric
pathogens distributed globally 1980 Human T-lymphotropic
10

Virus _—__ T-cell lymphoma-leukemia

virus I (HTLV-1)
1981 Toxic producing strains

of Staphylococcus

aureus Bacteria Toxic shock syndrome (tampon use)
1982 Escherichia coli

O157:H7 Bacteria Hemorrhagic colitis; hemolytic

uremic syndrome

1982 HTLV-II Virus _—_ Hairy cell leukemia

1982 Borrelia burgdorferi Bacteria Lyme disease

1983. Human immunodeficiency Virus Acquired immunodeficiency
virus (HIV) syndrome(AIDS)

1983 Helicobacter pylori Bacteria Peptic ulcer disease
1985  Enterocytozoon bieneusi Parasite Persistent diarrhea
1986 Cyclospora cayatanensis Parasite Persistent diarrhea

1988 Human herpesvirus-6 Virus Roseola subitum
(HHV-6)

1988 Hepatitis E Virus _—_Enterically transmitted non-A,
non-B hepatitis

1989 Ehrlichia chafeensis Bacteria Human ehrlichiosis

1989 Hepatitis C Virus Parenterally transmitted non-A,
non-B liver infection

1991 Guanarito virus Virus | Venezuelan hemorrhagic fever

1991 Encephalitozoon hellem Parasite Conjunctivitis, disseminated
disease

1991 New species of Babesia Parasite Atypical babesiosis

1992 Vibrio cholerae 0139 Bacteria New strain associated
with epidemic cholera

1992 Bartonella henselae § Bacteria Cat-scratch disease; bacillary
angiomatosis
11

1993 Sin nombre virus Virus Adult respiratory distress

syndrome
1993 Encephalitozoon
cuniculi Parasite Disseminated disease
1994 Sabia virus Virus _ Brazilian hemorrhagic fever
1995 HHV-8 Virus Associated with Kaposi sarcoma

in AIDS patients

Goeth more work Timeline. Mostly derived from Nobel Prizes (*) and the ASM poster.
The prizes * often postdate the discoveries by 10-20 years

1346 - initiation of Black Death in Europe

1492 - Columbus initiates European conquest of America

1546 - Fracastoro -- On contagion

1637 - Cinchona bark (quinine) brought to Europe for malaria

1684 - Jenner observes bacteria with new microscope

1798 - Jenner, vaccination

w++--------------- current millenium ----------------- 1877 - Patseur & Koch, initiate studies of

1892 Ivanowski, Dmitri: Discovers tobacco mosaic disease

1893 Smith, Theobald and F. L. Kilbourne: ticks carry Babesia microti;

1900 Reed, Walter: yellow fever is caused by mosquitoes; mosquito eradication programs
were begun

1901 * VON BEHRING, EMIL ADOLF "for his work on serum therapy, especially its
application against diphtheria

1902 * ROSS, Sir RONALD "for his work on malaria
1905 * KOCH, ROBERT "for his investigations and discoveries in relation to tuberculosis"

1907 * LAVERAN, CHARLES LOUIS ALPHONSE "in recognition of his work on the role
12

played by protozoa in causing diseases"

1908 * METCHNIKOFF, ELIE * EHRLICH, PAUL "in recognition of their work on
immunity”

1913 * RICHET, CHARLES ROBERT "in recognition of his work on anaphylaxis"
1915-17 Twort, Frederick, then Felix d’Herrelle discover bacteriophage.

1918 Epidemic of Spanish flu causes 40 million deaths in Europe (1918- 1919)
1919 * BORDET, JULES "for his discoveries relating to immunity"

1927 * WAGNER-JAUREGG, JULIUS therapeutic use of malaria inoculation in treatment of
syphilis

1928 * NICOLLE, CHARLES JULES HENRI "for his work on typhus"
1928 Griffith, Frederick:discovers genetic transformation phenomenon in pneumococci
1939 * DOMAGK, GERHARD "for the discovery of the antibacterial effects of prontosil"

1941 - bacterial viruses visualized by electron microscope Ruska, Helmut; using
microscope invented by Ernst Ruska

1944 Avery, Oswald, Colin MacLeod and Maclyn McCarty: discover that DNA is the
transforming principle

1945 * FLEMING, Sir ALEXANDER * CHAIN, Sir ERNST BORIS * FLOREY, Lord
(HOWARD WALTER) "for the discovery of penicillin and its curative effect in various
infectious diseases"

1951 * THEILER, MAX "for his discoveries concerning yellow fever and how to combat it"

1952 * WAKSMAN, SELMAN ABRAHAM "for his discovery of streptomycin, the first
antibiotic effective against tuberculosis”

1954 * ENDERS, JOHN FRANKLIN * WELLER, THOMAS HUCKLE * ROBBINS,
FREDERICK CHAPMAN " cultivation of viruses in cell cultures

1958 * BEADLE, GEORGE WELLS * TATUM, EDWARD LAWRIE genes act by
regulating definite chemical events"; * LEDERBERG, JOSHUA genetic recombination in
bacteria

1959 * OCHOA, SEVERO * KORNBERG, ARTHUR "enzymology of biological synthesis of
RNA and DNA
13

1960 * BURNET, Sir FRANK MACFARLANE * MEDAWAR, Sir PETER BRIAN "acquired
immunological tolerance"

1962 * CRICK, FRANCIS HARRY COMPTON * WATSON, JAMES DEWEY * WILKINS,
MAURICE HUGH FREDERICK DNA is a double helix

1965 * JACOB, FRANCOIS * LWOFF, ANDRI * MONOD, JACQUES " genetic control of
enzyme and virus synthesis"

1966 * ROUS, PEYTON "discovery of tumor-inducing viruses";

1969 * DELBRCK, MAX * HERSHEY, ALFRED D. * LURIA, SALVADOR E.
"replication mechanism and the genetic structure of viruses"

1972 * EDELMAN, GERALD M. * PORTER, RODNEY R. "chemical structure of
antibodies"

1973 Cohen, Stanley, Annie Chang, Robert Helling and Herbert Boyer: use of plasmids as
cloning vectors in genetic engineering

1975 * BALTIMORE, DAVID * DULBECCO, RENATO * TEMIN, HOWARD MARTIN
“tumour viruses and the genetic material of the cell; reverse transcription"

1976 * BLUMBERG, BARUCH S. * GAJDUSEK, D. CARLETON hepatitis and atypical
slow viruses.

1979 Smallpox eradication program of WHO completed
1980 * BENACERRAF, BARUJ * DAUSSET, JEAN * SNELL, GEORGE D. antigen
presentation and histocompatibility in immune response.

1981 AIDS first identified as a new infectious disease

1983 Montagnier, Luc and Robert Gallo: discover the HIV virus that is believed to cause
AIDS

1984 * JERNE, NIELS K. * KVHLER, GEORGES J.F. * MILSTEIN, CISAR " immune
networks and monoclonal antibodies

1987 * TONEGAWA, SUSUMU "for his discovery of the genetic principle for generation of
antibody diversity”

1995 Venter, Craig, Hamilton Smith, Claire Fraser and TIGR colleagues: elucidate the first
complete genome sequence of a microorganism

1996 * DOHERTY, PETER C. * ZINKERNAGEL, ROLF M. "for their discoveries
14

concerning the specificity of the cell mediated immune defence"

1997 * PRUSINER, STANLEY B. "for his discovery of Prions * a new biological principle
of infection"