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Dr. Colwell's Remarks


"From Cholera to Complexity to Society:
A Journey to New Dimensions"

Dr. Rita R. Colwell
National Science Foundation
DIMACS International Conference on
Computational and Mathematical Epidemiology
Rutgers University

June 29, 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 with math pattern background]
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Good morning, everyone. I'm very pleased to be here and I want to thank all of you for your patience in accommodating the changes in my schedule. I would especially like to thank you, Simon, for a kind introduction.

This conference focuses on a very timely intersection of disciplines: computational and mathematical epidemiology. We hear a great deal of talk these days about interdisciplinary research; indeed, last weekend I spoke at the University of California-Santa Cruz on how and why the National Science Foundation supports interdisciplinary research.

The meeting here makes it concrete--a compelling convergence of disciplines, drawing together computer scientists, mathematicians and biologists to focus on intersecting challenges of great consequence to society.

This meeting is also timely in its implications for the biological security of this nation and the globe. Most of you will not need reminding that confronting infectious disease and potential bioterrorism draws on similar tools and methodologies. In the post-September 11 world, such work takes on new urgency.

These two themes--interdisciplinarity and homeland security--are highly intertwined and they will provide context for my talk today. Within this framework, I will begin with a case study of my own work on cholera and the complexity of its ecology, and then move to a broader discussion of how the intersection of mathematics and biology has implications for homeland security.

[Cover of the book, Flatland]
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When I consider how our understanding of cholera's relationship to its environment has evolved in complexity over recent decades, I am reminded of the classic book, Flatland, written by Edwin Abbott Abbott well over a hundred years ago.

Many of you may recall this ageless parable on how beings from one dimension meet those from another--how the narrator, a mathematician who inhabits a land of two dimensions, visits a lower world, where everything looks like a point, and finds it terribly impoverished, compared to the lines and angles that enrich his own level.

Then, of course, he makes a visit to a three-dimensional world--and sees, for the first time, his own, now-diminished world from another vantagepoint. His subsequent attempts to convert others in Flatland to the vision of three dimensions come to naught.

He finally writes his travel memoirs, hoping to "stir up a race of rebels who shall refuse to be confined to limited dimensionality."

The Flatlander's view provides an analogy for the limited concept of infectious disease that has existed for a long time--a picture that considers pathogens isolated from their environmental context. We cannot afford such myopic vision today, when social and environmental changes are often key factors in the appearance of emerging and reemerging diseases.

[cholera bacterium]
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Vibrio cholerae, the causative agent of cholera, is a case example of a pathogen with a complex ecology that must be understood in order to deal with the disease. We have only recently begun to grasp the complexity pervading the relationship of cholera to its environment.

Until the 1970s, virtually all studies of the organism in the environment were based on methods developed for clinical diagnosis of cholera in hospital laboratories--that is, methods to culture cells.

Today, however, we have the tools to detect cholera in its natural environment. We have been able to sketch a much fuller picture of cholera by drawing insights from many disciplines, including mathematics and computing. We've also sought understanding at many different scales, from the molecular level to the satellite view.

[Cholera statistics, 2000: WHO]
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As you know, cholera is still an enormous scourge in developing countries. 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.

To give an idea of possible worldwide totals, especially during epidemics, a representative year is 1991, when more than 200,000 cases were counted in three months in Bangladesh alone. From August through November of that year, a thousand cholera victims entered the hospital daily in Dhaka, Bangladesh.

[Map of cholera spread from old medical textbook]
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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 actually 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. However, almost everything we know about it is very recent.

[Map: Global spread of cholera, 1961-91]
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In more recent times, cholera has affected human populations and cultures in as many as eight major pandemics, with its first documented occurrence in 1817 around Persia. The map summarizes the epidemic years of the seventh pandemic, which began in Celebes -- in Indonesia--in 1961.

A new biotype called El Tor emerged in Madras, India in 1991-1992 to replace the one that had been predominant before. Subsequently, a new serotype of V. cholerae--0139--emerged as an epidemic form.

In endemic regions, cholera appears seasonally. As we now know, environmental, seasonal and climatic 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.

[Chesapeake Bay cholera sampling sites]
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In the late 1960s, 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 the water, the organisms may be dispersed and they may be dormant--not actively metabolizing. This characteristic--entry into a viable but nonculturable state--is shared, in fact, by many bacteria.

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

[copepod close-up]
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Here we see a copepod close up--a minute relative of shrimp, which forms part of the zooplankton. This microscopic animal lives in rivers and salt or brackish waters, and travels with currents and tides.

Copepods harbor dormant, nutrient-deprived, and culturable vibrios. The bacteria can survive as an inactive, spore-like form in the gut and on the surfaces of the copepods between epidemics.

This copepod is a female whose egg case is covered with vibrios. Cholera colonizes mostly the oral region and egg sacs of copepods.

Our hypothesis, in fact, is that cholera originally evolved commensally with marine animals such as copepods, which provided them a surface to grow and perhaps other mutual benefits. One such advantage is that as the copepod's egg sac ruptures in the water, the cholera bacteria are dispersed with the eggs. In turn, the copepod or other hosts may benefit from the highly proteolytic capability of the vibrios--in rupturing the egg sac, for example.

[graph: V. cholerae numbers on copepods]
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A single copepod can harbor as many as 10,000 Vibrio cholerae. The infectious dose is 1066, so 100 copepods, if ingested, would carry an infectious dose. 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.

We also know that cholera in its nonculturable but viable state can revert back to being culturable and infectious after passage through the human gut, as well as in the environment. Now we seek to better understand the genetic regulation strongly suspected to control passage into and out of the "somnolent" state.

Since the aquatic environment is the reservoir for cholera, it can certainly be the source of novel pathogenic strains arising in the future through microevolution. Cholera is a very dynamic organism, with lateral transfer of genetic material occurring between organisms in the wild.

Yet, only two serotypes out of a couple of hundred have been involved in epidemics to date. We have learned that cholera genes can transfer rapidly between two habitats--the human gut and water.

As I've already mentioned, a new serotype--0139--emerged in 1992, and it causes explosive outbreaks. Before this, non-01 serotypes were not known to cause diarrhea epidemics. This is a significant turning point in the history of cholera because the evidence points to this strain arising from genetic recombination and horizontal gene transfer, and the acquisition of unique DNA through introduction of a block of foreign genes.

[cholera outbreaks, SST and SSH]
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The story of cholera extends from the microscopic to the planetary. Taking a global view, cholera and climate are intimately linked. We know that cholera epidemics are seasonal. Using remote sensing imagery, we recently discovered that, in 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 occuring soon after across South America. Based on our data analyses now being prepared for publication, we believe that the El Nino climate pattern produced conditions conducive to a cholera outbreak.

[woman with sari cloth filter]
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We seek to apply our knowledge to alleviate and even predict the rise of cholera. Certainly we've learned that environmental and clinical samples can no longer be considered free of pathogens simply because a culture is negative. Even though pathogens may not be culturable from river or brackish water, such water used for drinking or washing fruits and vegetables actually poses serious risk of infection.

In fact, 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.

At the same time, mathematics and computing have supplied critical insights into the cholera puzzle, from the molecular level to social studies in the villages of Bangladesh to remote sensing of sea surface temperature in the Bay of Bengal or the Pacific Ocean. All contribute critical elements to cholera epidemiology.

(Use "back" to return to the text.)

This complex case of an infectious disease--cholera--linked to climate, has helped me to formulate a philosophy called biocomplexity. The cholera story, still to be fully unravelled, embraces environmental factors from the cellular level to the scale of global climate.

It has helped to engender the concept of biocomplexity--the dynamic web of interrelationships that arise when living entities at all levels, from genes to human beings to ecosystems, interact with their environment.

Biocomplexity's linkages to medicine have ancient roots. Hippocrates himself wrote that "Whoever wished to investigate medicine properly should...consider the seasons of the year..., the winds..., the qualities of the water..." Epidemiology and ecology have vast common ground.

[static and dynamic approaches to public health]
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Here we see one framework for thinking more dynamically, and realistically, about infectious disease. The white triangle depicts the 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.

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.

[NEON map]
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What lessons can we take from a case study of an infectious disease viewed in its environmental context? For one, we 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. A protoype site might comprise a university, a Nature Conservancy site, a national park, and other locations.

[instrumenting the environment]
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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.

[the microbial world]
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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.

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.

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 as markers of potential genetic engineering. If a pathogen becomes modified by a bioterrorist to make it even more deadly, how will we know?

[Business Week column headline on math/natl. security]
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Mathematics has tremendous potential to help us deal with such threats. The public, however, may not grasp the link between security and support for mathematics--another challenge for those of us who do: to explain it.

In April, the National Research Council sponsored a workshop on the role of the mathematical sciences in homeland security. The workshop was mind-expanding for some, such as Howard Schmidt, from the President's Critical Infrastructure Protection Board.

As he told Business Week, "When I got the e-mail invitation, I thought at first it was a joke." As the conference proved, however, mathematics can provide deep insights into many challenges of homeland security, from protecting computer infrastructure to dealing with bioterrorist threats.

[New Types of Problems: word slide]
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The workshop recognized several new kinds of security problems that mathematical solutions could alleviate. These problems reverse older viewpoints and include: searching for rare events instead of common patterns; protecting systems from malicious attacks instead of random failures; and combining data from many types of sources.

[Math Research Challenges in Homeland Security: word slide]
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As a next step, the workshop identified these four major research challenges for mathematics related to homeland security. They are: data mining for rare events; computer, network and physical infrastructure security; detection and epidemiology of bioterrorist attacks; and voice and image recognition.

Many of these areas, I notice, have linkages to the themes discussed in this conference.

[graph analyzing hands in different positions]
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Well before September 11 the National Science Foundation identified information technology and mathematics as priority areas for focused, interdisciplinary funding. I will cite a few examples of NSF-backed research that is already underway - mathematics research projects that exemplify how we are already tackling some of these security challenges.

In the realm of dealing with large data sets, here is a graph analyzing images of hands in different positions. These data are not amenable to classical linear methods of analysis. How do we--and how can a computer--recognize all of these images as a hand, even when rotated into many different positions?

Just so, how do we recognize a face when lighting and expression change, and how can we tell a computer to do that? How can the brain look at the many measurements an object can possess--and select only the dimensions that vary, thereby zeroing in on what matters? This work by Gunnar Carlsson and Joshua Tenenbaum at Stanford University and their colleagues cut a problem with many dimensions down to size.

Image restoration and recognition are making great progress with insights from mathematics and computing. As an example, a technique called "inpainting" borrows techniques from classical fluid dynamics to use a computer to fill in missing pieces of a digital image, whether of a fine painting, an old movie or the blurry face of a criminal suspect. There are many other such techniques being developed, with representative results shown here.

[Sir Martin Rees and Dracula: two images side by side]
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Let's move to connectivity, as suggested in this unlikely pair of images. "What do the Astronomer Royal and Dracula have in common?" asked a headline in the British newspaper Independent. (Sir Martin Rees, Britain's astronomer royal, is on the left.) A further question could be: what could they both possibly have in common with epidemiology and tracking bioterrorism?

The answer: connectivity. Both the astronomer royal and the actor Christopher Lee, who has starred as Dracula, are the most "connected" within their respective communities. As discovered by Mark Newman of the Santa Fe Institute, the astronomer has collaborated most widely of anyone in astrophysics, while Lee is the actor most linked to other actors.

Newman studies many sorts of networks--mathematical theory that applies to the World Wide Web, collaborations among scientists, networks of company directors.

As he notes, "Networks of physical contact between people also govern the way diseases spread. A proper understanding of the nature and progress of epidemics is impossible without good network models."

[two types of networks, stylized; from Mark Newman]
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Here is an excellent illustration from Newman's work that depicts how connected people are. On the left we see one type of network-depicting a core group of highly connected people. On the right is another type of network, less centrally organized.

Now, a strategy to control disease is to find highly connected people and to treat them. It turns out that this works exceptionally well with the case on the right--but not in the network on the left.

"Unfortunately," says Newman, "most social networks--the networks over which diseases spread--seem to fall into the category on the left. This suggests that our current simple strategies for tackling the spread of infection may not be effective. With new understanding, however, we may be able to suggest effective targets for immunization or education campaigns to slow disease spread." What a timely application of mathematics to current challenges.

[ending collage]
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As I close I'll mention some other developments related to mathematics at the National Science Foundation. We now have a joint program with the National Institutes of Health on mathematical biology, currently funded at $6 million.

In addition, to help strengthen the mathematical sciences as the backbone for U.S scientific and engineering research, we are in the process of announcing three new research institutes.

The first is the Mathematical Biosciences Institute at Ohio State University, announced just two days ago, which will focus on mathematical bioscience, exploring interdisciplinary problems such as neuroscience and cell processes.

Postdoctoral scientists at the institute will be mentored jointly by a bioscientist and a mathematician. The two other centers, to be announced shortly, will double the number of such institutes we support to a total of six.

Let me close now by returning to where I began, after a visit to many dimensions--the complexity of cholera, the need to connect medicine to ecology, and the fertile juncture of mathematics and biology.

I recall now that inhabitant of Flatland who hoped that his journeys to other worlds would cause readers to rebel against commonplace views and to explore new dimensions.

I'll echo that hope of connecting to new disciplines and dimensions for all of us at this conference, and now I'll be happy to take any questions or comments you might have.



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