"From Cholera to Complexity to Society:
A Journey to New Dimensions"
Dr. Rita R. Colwell
Director
National Science Foundation
DIMACS International Conference on
Computational and Mathematical Epidemiology
Rutgers University
June 29, 2002
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[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.
[biocomplexity]
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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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