"Biocomplexity: A New Paradigm for Infectious Disease"
Dr. Rita R. Colwell
National Science Foundation
Harvard/MIT Conference on Infectious Disease
March 9, 2002
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I have never heard a more eloquent introduction. It
augurs well for the conference.
Good morning to all. It's a pleasure to be a guest
of the Harvard and MIT Hippocratic Societies and also
to be among such distinguished company, many of whom
are friends of long standing. I am delighted to deliver
your keynote address today to open the Harvard-MIT
Conference on Infectious Disease.
The program for the conference indicates some very
exciting and broad-ranging topics to be covered. Therefore,
I'd like to suggest a new framework for viewing infectious
It's called biocomplexity. The term describes
the study of complex interactions in biological systems,
including humans, and between those systems and their
We know that ecosystems do not respond linearly to
environmental change. We also know that understanding
demands observing at multiple scales, from the nano
to the global. Complexity principles emerge at various
levels, whether studying a cell, a human body, or
Biocomplexity has ancient roots. Hippocrates himself
wrote that "Whoever wishes to investigate medicine
properly should...consider the seasons of the year...,
the winds,...the qualities of the waters..." Epidemiology
and ecology have a vast common ground.
[Deer mouse and
landscape in Sevilleta]
I'll begin with a story. It encapsulates the approach
of biocomplexity applied to infectious disease. Many
of you are, I'm sure, familiar with its outline.
It began in 1993 in the Four Corners area of the United
States, when young and otherwise healthy people began
dying from an unknown disease. At the time, in fact,
some suspected bioterrorism.
The culprit turned out to be a Hantavirus unknown in
the New World until the outbreak. The mortality rate
of those infected with the virus--more than 50%--is
second only to Ebola. Was the new virus a mutant,
or had the environment been harboring it all the time?
The carrier turned out to be a rodent, the deer mouse
pictured here. Biologists working at an NSF-supported
Long-Term Ecological Research site, led by Terry Yates
of the University of New Mexico and his team, were
able to detect the deadly virus in mouse tissue that
had been archived years before. As it happened, Native
American legends corroborated a history of outbreaks.
In addition, the investigators showed a link between
climate and the outbreak of disease. Mild and wet
winters associated with a periodic climate pattern,
El Niño-Southern Oscillation, had provided
more food for the rodents, whose populations had increased
dramatically in 1993.
[Trophic cascade graph; slide is not available]
Eventually, researchers found a time lag between the
rodent population increase and the increase in human
The green bars show the human cases of Hantavirus infection
over time. The black line denotes the increase in
the mice populations.
It turns out that there is a time lag between the peaking
rodent populations and the increase in disease incidence.
The key predictor of disease cases is not the increase
in numbers of rodents, but the increase in infected
rodents, shown here in red. (I would like to thank
Terry Yates for lending me these slides showing his
[Phylogeny of hantaviruses; slide is not available]
We have learned that hantaviruses generally have evolved
closely with their rodent hosts. Looking at this phylogenetic
tree, on the left we see various viral strains, and
on the right the rodent species that host each one.
The hosts and the microorganisms speciated together.
[Hantaviruses in North and South America; slide
is not available]
Here we see a map of New World hantaviruses. All but
one have been discovered since 1993. They were here
all the time but we just didn't know it.
Here is an object lesson in the need to understand
biocomplexity before we can assume that we really
know what is "out there," let alone predict an outbreak
or even be able to identify an attack of bioterrorism
for what it is.
[Canyon del Muerto; slide is not available]
In New Mexico, the researchers have now developed a
predictive model indicating areas of highest risk
Asking where the virus "hides" between outbreaks,
they have begun to develop "ground truth" for refugia.
Canyon del Muerto, pictured here peppered with red
dots, seems to be a likely place for hantavirus to
exist for years beyond human awareness.
[Ship and Aldo
The prophet of ecology, Aldo Leopold, counseled that
we must "convert our collective knowledge of biotic
materials into a collective wisdom of biotic navigation."
The Hantavirus story--just one compelling chapter in
the saga of ecology and infectious disease--exemplifies
the need to be able to trace complexity in order to
Our new tools--genomics, information technology, complexity
theory--are launching us for the first time on a journey
to trace the coastlines of our biocomplex world. Such
understanding will open the new frontiers of environmental
prediction. The infrastructure and approaches developed
to understand infectious disease also poise us to
confront the threat of bioterrorism.
Interactions between health and environment, whether
natural or nefarious in origin, span scales of space
and time. For example, the earth's climate acts on
a global scale, while decisions on human health are
[Static and dynamic
approaches to public health]
Here we see one framework for thinking more dynamically,
and realistically, about infectious disease, and I
thank Mark Wilson of the University of Michigan for
The white triangle depicts infectious-disease agent,
host, and environment frozen in time and space. In
this model, we tend to wait for clinical cases to
appear before public health measures are taken.
A more dynamic view--the colored triangle--suggests
the complexity of the real world, with time lags,
feedbacks, and interactions across scales.
Such an approach contradicts the linear, simplistic
notion that we can successfully eradicate a disease
from the face of the planet.
At the same time, as we plot these complex links, and
recognize signals from climate models and incorporate
them into health measures, new opportunities arise
for proactive--rather than reactive--approaches to
digital and bacterial evolution]
The synthetic perspective of biocomplexity brings surprising
insights into the process of evolution.
In a project currently supported by NSF, a microbiologist
at Michigan State, Richard Lenski, has joined forces
with a computer scientist and a physicist to study
evolution in action, using two kinds of organisms--bacterial
They watch how biological complexity evolves in two
contrasting systems. Lenski's E. coli cultures
are the oldest of such laboratory experiments, spanning
more than 20,000 generations.
Here the two foreground graphs actually show the family
tree of digital organisms--artificial life--evolving
over time. On the left, the digital organisms all
compete for the same resource, so they do not diversify
and the family tree does not branch out.
On the right, the digital organisms compete for a number
of different resources. Deep branches develop in that
family tree over time.
In the background are round spots--actually laboratory
populations of the bacterium E. coli, which
also diversified over time when fed different resources.
In vivo derives insight from in silico.
[Tree of Life:
You are here]
Fundamental research in microbial ecology spawns insight
for public health dilemmas. As we survey the natural
world with an ecological lens, we learn a lesson of
great humility. In the words of Edward O. Wilson,
one of Harvard's own biological treasures, "We have
only begun to explore life on Earth."
He continues, "The vast majority of the cells in your
body are not your own; they belong to bacterial and
other microorganismic species."
As put by one of microbiology's foremost revolutionaries,
Carl Woese, a new microbiology arrived on the doorstep
of the new millennium. Gone are the notions that life
should be divided into five kingdoms or bisected into
prokaryotes and eukaryotes.
Thanks to Woese, all of life can be depicted in a universal,
phylogenetic tree, based on ribosomal RNA, a molecule
ubiquitous to life and highly conserved in evolution.
The division of the tree into three domains reveals
that the vast history and diversity of life is microbial,
offering great ramifications for understanding emerging
[W. Martin's E. coli evolution fig.; slide
is not available]
This figure depicts genes flowing in and out of the
E. coli chromosome over time. Microorganisms
evolved by sharing their genomes to a startling extent.
As part of biocomplexity, NSF has begun a program to
assemble the genealogical Tree of Life, including
tracing the web-like connections among lineages that
result from horizontal gene transfer.
We expect the tree will do for biology what the periodic
table did for chemistry and physics--provide an organizing
framework. It will also help us track emerging diseases
and their vectors.
Project: report cover]
Advances in genomics also bring powerful tools to bear
upon public health and ecological challenges alike.
A Federal interagency group including NSF supports
"The Microbe Project," a coordinated effort in microbial
Genomics offers unprecedented opportunity to begin
to probe a microbial world that is almost a complete
mystery. It will have immediate payoffs, too, such
as the sequencing of anthrax. Microbial genomics is
a major focus of NSF's biocomplexity budget proposal
Genomics, for the first time, offers the possibility
to identify "what's out there" ---such as what lives
in the rich communities around deep-sea hydrothermal
vents, where life may well have originated.
Although microorganisms constitute more than two-thirds
of the biosphere, they represent a great unexplored
Of bacterial species in the ocean, less than 1 percent
have been cultured. Just a milliliter of seawater
holds about one million of these unnamed cells.
Last November, scientists partly funded by NSF sequenced
DNA at sea for the first time. They sequenced creatures
from vent communities like those shown here, about
two miles deep in the Pacific Ocean.
Tubeworms, crabs and other vent-dwellers thrive there,
along with bacteria and archaea in water near or above
the boiling point.
of life around vents]
NSF and the National Institute of Environmental Health
Sciences are discussing how to connect this fundamental
research to our health.
For example, we know little about what happens to pathogens
in the marine environment. Indeed, seafloor sediments
may provide a long-term reservoir for pathogens. Some
ideas ripe for research include vector and water-borne
diseases, marine pharmaceuticals, and harmful algal
[Map of U.S.
HABs before and after 1972]
Harmful algal blooms are a serious marine hazard for
humans and other life forms. This map shows the increase
in their occurrence around the U.S.
More than 60,000 human infections occur each year in
the U.S. alone, caused by toxins that exist at the
limit of detection.
[Collage of HAB
These organisms share interesting traits with pathogens
that cause infectious disease: both induce disease
by the toxins they produce. As the environment changes,
these algal blooms may be on the increase.
[Table of diseases
with environmental links]
Environmental change, of course, will also affect agents
of infectious disease. Global change could nudge pathogens
and vectors to new regions. Agents of tropical disease
could drift toward the polar regions, creating "emerging
diseases" at new locales.
This table gives examples of some diseases--relayed
by vectors, water, food, air or otherwise--that interact
with climate. One important climate pattern--El-Nino
Southern Oscillation---has been linked to outbreaks
of malaria, dengue fever, encephalitis, diarrhoeal
disease, and cholera.
These leaps of discovery to the new frontiers of microbiology,
using diverse evidence from climatology, genomics,
and information technology, make it possible to tell,
with some confidence, stories about specific diseases.
I began today with the story of hantavirus pulmonary
syndrome. Let's now focus the lens of biocomplexity
on three other emerging and reemerging diseases, whose
tales are interwoven with ecological change and climate
ENSO, malaria and Venezuela]
The first is malaria, a disease ripe for the perspective
of biocomplexity. Forty years ago, we thought we had
defeated human malaria. Today, hundreds of millions
of people are infected each year. Among vector-borne
diseases, malaria is one of the most sensitive to
It is hosted by many species of anopheline mosquitoes
in a variety of larval habitats, from puddles to swamps
to brackish water.
Warming temperatures may be expanding malaria's reach.
Its spread has many puzzling features, as it moves
to untraditional locations such as highlands and urban
areas, for reasons we do not understand. Old models
of malaria, from a century ago, no longer suffice.
I would like to focus the biocomplexity lens on one
particular project, which is developing models of
avian malaria in Hawaii, a microcosm that
may have lessons for the more complex global issues
of human malaria.
Neither malaria nor mosquitoes are native to the Hawaiian
Islands. Since the system involves introduced disease,
it also serves as a model for emergent mosquito-born
diseases such as West Nile Virus in North America.
The project team is led by David Duffy of the University
Hawaiian rainforests have lost half their bird species
to extinction since Europeans arrived. Diseases--malaria
and avian pox carried by introduced mosquitoes--are
thought to be a major cause.
Mauna Loa on the Big Island rises from coral reef,
through forest, up to permafrost, furnishing a laboratory
to study malaria in different habitats.
As urbanization encroaches on the forest, mosquitoes
gain habitat. The feral pig, also introduced into
Hawaii, creates mud wallows and hollows out ferns;
both collect water that offers mosquito-nesting habitat.
Different strains of malaria afflict birds, and one
bird can carry several strains at one time. Many mainland
U.S. birds are immune to malaria, and some Hawaiian
birds may be evolving resistance as well.
Learning the complexities of scale and time, and of
integrations among host, vector and environment, should
lead to better models of malaria.
"We're finding complexities in avian malaria that were
unimaginable five years ago," says Duffy.
"It used to be thought that altitude explained the
spread of malaria. Now, we ask, are there weak links
in the cycle of the parasite or the mosquito? What
is the ecological scale at which to intervene in this
"There may be some interplay of malaria and host genetics
with climate that we can exploit to save the last
Hawaiian birds, while providing a paradigm to manage
human malaria," he concludes.
Influenza is another disease with undiscovered environmental
complexities. We all know influenza outbreaks are
seasonal, but we really don't know why.
Climate is suspected to shape the seasonal cycles of
influenza in some way, although a direct link with
temperature is too simple. Outbreaks fluctuate greatly
from year to year; the 1918 Spanish flu killed more
than 20 million people.
We know that influenza "changes its cassette" almost
with every sneeze--it is constantly evolving, at great
speed, and subtle mutations let the virus infect those
who had it before. New strains emerge, circulate globally,
and replace old strains.
Influenza occurs not only in humans but also in chickens,
ducks, other birds, seals, swine, and horses. Scientists
keep a watch on poultry markets. In 1997, one virus
led to the slaughter of 1.3 million chickens in Hong
Kong. Human influenza A originated in birds, but is
closely related to that of swine, and is thought to
have jumped from birds to swine to humans. When the
virus crosses species to a new host, it evolves much
more quickly. We have much to learn about influenza's
complexities, and whether better climate predictions
might help with forecasting disease outbreaks.
My own research on cholera tells yet another story.
My voyage of discovery, the study of how factors combine
to cause cholera, began more than 30 years ago. In
endemic regions, cholera appears seasonally.
As we now know, environmental, seasonal and climate
factors influence the populations of the larger host
organism for cholera, the copepod. It peaks in abundance
in spring and fall.
Add in economic and social factors of poverty, poor
sanitation, and unsafe drinking water, and we begin
to see how this microorganism sets off the vast societal
traumas of cholera pandemics.
We explore the problem on different scales. We study
the relationship among bacteria, its copepod host,
and many other ecological and social factors. On a
microscopic level, we look at molecular factors related
to the toxin genes in vibrios.
It is an enormous challenge. The latest numbers of
cholera cases from the World Health Organization are
for the year 2000: 137,071 cases and almost 5,000
But note that those figures don't include Bangladesh,
Pakistan, both North and South Korea, and several
other countries, whose aggregate numbers may equal
those reported for the rest of the world, shown in
spread of cholera, 1961-91]
The map summarizes the epidemic years of the seventh
pandemic, which began in the Celebes in 1961. There
is now consideration that an eighth pandemic may be
in the offing, since a new serotype of V. cholerae--0139--has
emerged as an epidemic form.
[Map of cholera
spread from old medical textbook]
This map, tracing the path of cholera's spread, is
taken from an 1875 medical textbook. One sees little
change today in the areas where cholera is endemic.
But cholera is much older than that. A disease similar
to cholera was first recorded in Sanskrit writings
in what is now India about 2,500 years ago. But almost
everything we know about it is very recent.
cholera sampling sites]
In the 1970s, my colleagues and I realized that the
ocean itself is a reservoir for V. cholerae,
including V. cholerae 01, when we identified
the organism in water samples from the Chesapeake
Earlier detection methods for V. cholerae 01
were developed strictly for testing clinical samples,
and they do not give information on the frequency
of occurrence or activity of a taxon in the environment.
In environmental samples, V. cholerae 01 is
more difficult to detect. The organisms may be more
dispersed in the water and they may be dormant--not
Our latest results using in situ sampling
in the Chesapeake show a patchy distribution of some
bacteria and seasonal abundance in association with
Here we see a copepod close up--the minute relative
of shrimp which forms part of the zooplankton populations.
This microscopic animal lives in salt or brackish
waters and travels with currents and tides.
Copepods harbor both dormant, nutrient-deprived, and
culturable vibrio. The bacteria can survive as an
inactive, spore-like form in the guts and on the surfaces
of the copepods between the epidemics.
This copepod is a female whose egg case is covered
with vibrios. The vibrio can be cultured somewhat
more easily in the summer months.
cholerae numbers on copepods]
In fact, a single copepod can harbor as many as 10,000
Vibrio cholerae cells. Most recently, we
have used genetic techniques--PCR and gene probes--to
detect Vibrio directly from environmental
samples, confirming earlier immunofluorescent detection
results employing monoclonal antibodies.
SST and SSH]
We know that cholera epidemics are seasonal. Using
remote sensing imagery, we recently discovered that,
in areas of Bangladesh, cholera outbreaks occur shortly
after sea surface temperature and sea surface height
are at their zenith. This usually occurs twice a year,
in spring and fall.
After a century without a major outbreak of cholera,
a massive Vibrio cholerae epidemic occurred
in the Western Hemisphere in the El Nino year of 1991,
starting in Peru and spreading across South America.
[Woman with sari
Cholera transmission is easily controlled by providing
people with clean, uncontaminated water for drinking
Even at the most basic level, we have found that filtering
water through several layers of sari cloth may be
enough to prevent ingestion of infectious levels of
V. cholerae by removing the particulate matter,
including the zooplankton--the copepods.
As my group's research with Vibrio cholerae
has shown, what appears to be a tightly circumscribed
biological problem-a bacterium that infects people--can
have ramifications and interrelationships on a global
[Graph: the increasing
value of data]
What lessons can we take from these case studies of
infectious diseases viewed in their environmental
contexts? One sure precept is that long-term data,
from both epidemiology and ecology, are vitally needed.
Only with the temporal perspective can we merge the
best of ecology and health research. This impressionistic
graph of data value over time helps us think about
how to design our data networks, and I am thankful
to Jim Gosz of the University of New Mexico for lending
I draw your attention particularly to the lines for
increasing value. Data might lead to a serendipitous
discovery that increases its value--recall the rodent
tissue samples that proved to harbor hantavirus. The
syntheses of data from different sites also increase
value above that from one site alone.
NSF supports a Long-term Ecological Network across
the United States and beyond. The map shows countries
with LTER networks, those awaiting formal recognition
from their governments, and those that have expressed
interest in developing a network.
In fact, it was studies at an LTER site at Sevilleta,
New Mexico that cracked the case on hantavirus in
From the health standpoint, it is unfortunate--as noted
by the American Academy of Microbiology--that systematic
disease surveillance is being abandoned, including
in the United States.
The situation for long-term surveillance of key pathogens
in the environment is even worse. To track infectious
disease, and now potential bioterrorism, we need committed
surveillance of disease, ecology and climate.
We also need a much richer understanding of how organisms
react to environmental change. Today, we simply do
not have the capability to answer ecological questions
on a regional to continental scale, whether involving
invasive species or bioterrorist agents.
In this context, NEON--the planned National Ecological
Observation Network--will be invaluable. This is a
schematic portrayal of NEON, an array of sites across
the country furnished with the latest sensor technologies.
Here's an imaginative rendition of a NEON site fully
instrumented (with apologies to the artist Rousseau).
Networks such as NEON require state-of-the-art sensors
of every stripe.
Such a site will measure dozens of variables in organisms
and their physical surroundings. All the sites would
be linked by high-capacity computer lines, and the
entire system would track environmental change from
the microbiological to the global scales.
[Out of the box]
If we think "out of the box," as this graphic shows,
LTER, NEON and biocomplexity weave many dimensions
together into a greater whole. Long-term research
brings in the dimension of time, NEON brings space,
and biocomplexity encompasses all the research parameters.
Our work today is global and urgent, and our world
is more than ever a microbial world. Pathogens do
not carry passports. As travel and the threats of
bioterrorism increase, monitoring for pathogens, diseases
and climate variables becomes all the more critical.
There are feedbacks, too; smallpox, once an infectious
disease problem, has become a bioterrorism threat
partly because of success with public health
If we do not understand the natural fluctuations in
our environment, we will not be able to spot signals
that are human-induced. A bioterrorism attack could
appear, in the beginning, like any other natural outbreak.
The anthrax scare had our laboratory staffs running
ragged. We also learned how little we knew about anthrax.
In the past, labs dealt mostly with hoaxes--more than
200 on anthrax and other supposed pathogens in 1999,
although there were said to be actual releases of
biotoxins in the past that were not publicized.
We need to develop much more sophisticated methods
to respond rapidly to potential bioterrorism; conventional
techniques, using culture, can take days to produce
We need fast methods such as real-time PCR, not only
to detect pathogens but also markers of potential
genetic engineering. If a pathogen becomes modified
by a bioterrorist to make it even more deadly, how
will we know?
To foretell events today, we attempt to read not tea
leaves but the messages of complexity.
To conclude this journey into biocomplexity and disease
on a poetic note, I would like to share an excerpt
from T.S. Eliot's "The Four Quartets."
Eliot evokes how humankind has used curiosity to "search
past and future" through the ages:
"To report the behaviour of the sea monster.../
Observe disease in signatures, evoke/
Biography from the wrinkles of the palm/
And tragedy from fingers...
To explore the womb, or tomb, or dreams; all these
are usual /
Pastimes and drugs, and features of the press;/
And always will be, some of them especially/
When there is distress of nations and perplexity..."
Surely we can reduce our perplexity, and progress on
the path to prediction in ecology and epidemiology,
by borrowing from each other's wisdom.