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Dr. Colwell's Remarks


"Biocomplexity: A New Paradigm for Infectious Disease"

Dr. Rita R. Colwell
National Science Foundation
Harvard/MIT Conference on Infectious Disease
Cambridge, Massachusetts

March 9, 2002

See also slide presentation.

If you're interested in reproducing any of the slides, please contact
The Office of Legislative and Public Affairs: (703) 292-8070.

[title slide]
(Use "back" to return to the text.)

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 disease.

[New biocomplexity spiral]

It's called biocomplexity. The term describes the study of complex interactions in biological systems, including humans, and between those systems and their physical environments.

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 an ecosystem.

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 infections.

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 latest results.)

[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 for hantavirus.

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 Leopold quote]

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 predict.

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 made locally.

[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 concept.

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 public health.

[Richard Lenski: 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 and digital.

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 infectious diseases.

[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.

[The Microbe 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.

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 this year.

[Life around undersea vents]

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 frontier.

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.

[Second shot 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 blooms.

[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 organisms]

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 patterns.

[Malaria pic: 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 climate.

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.

[Hawaiian biota collage]

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 of Hawaii.

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 disease system?

"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.

[cholera bacterium]

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.

[Cholera statistics, 2000: WHO]

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 deaths.

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 this slide.

[Map: Global 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.

[Chesapeake Bay 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 Bay.

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 actively metabolizing.

Our latest results using in situ sampling in the Chesapeake show a patchy distribution of some bacteria and seasonal abundance in association with zooplankton fluctuations.

[Copepod close-up]

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.

[Graph: V. 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.

[Cholera outbreaks, 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 cloth filter]

Cholera transmission is easily controlled by providing people with clean, uncontaminated water for drinking and bathing.

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 scale.

[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 it.

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.

[International LTER network]

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 1993.

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.

[NEON map]

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.

[Instrumenting the environment]

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.

[The microbial world]

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 eradication programs.

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 answers.

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?

[Biocomplexity spiral--again]

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.



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