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Dr. Colwell's Remarks


"A Voyage of Discovery: Cholera, Climate and Complexity"

Dr. Rita R. Colwell
National Science Foundation
The Eighth Lecture of "The Anatomy Lesson"
Amsterdam Concertgebouw

November 22, 2001

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.

Good afternoon to all and thank you for a gracious introduction. I extend my deep gratitude to the Academic Medical Center, to De Volksrant and to the University of Amsterdam for the opportunity to be here today. It is an honor and a great privilege to address you in this spectacular and historic setting of the Concertgebouw. The beautiful music we just heard has helped to set a maritime mood for my lecture today. Just as the sea has been a source of creative inspiration to the composer of these musical selections, it has been a source of inspiration as well as information for my life's work.

This research ultimately has linked the fluctuations of global climate to the dynamics of cholera, an infectious disease.

[title slide]
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In keeping with the oceanic atmosphere, I have titled my talk "A Voyage of Discovery: Cholera, Climate and Complexity." Appropriately for a scientific lecture named for a work of art, I will begin with some thoughts on how science and art converge to broaden our vision of the world. Each, in its own way, opens up new vistas.

Today's event celebrates a meeting of two worlds--art and science--that are too often viewed as separate realms. The famous American biologist E. O. Wilson points out that both art and science seek elegance--using pattern to fashion meaning from chaotic detail.

He writes, "Neither science nor the arts can be complete without combining their separate strengths. Science needs the intuition and metaphorical power of the arts, and the arts need the fresh blood of science."1

We need this exchange between the two worlds all the more so today, with the advent of the science of complexity, and its special derivative, biocomplexity. We study systems composed of many variables that are interdependent in surprising ways. What is more, these relationships are non-linear--they do not unfold in a straightforward way. Our increasingly sophisticated tools are essential to our ability to envision in science. They enable us to begin to grasp the complexity of our world--even let us connect climate to the patterns of infectious disease.

These two related themes--the revolution in our ability to see, and the birth of complexity science--embrace my own research. My own journey in science has brought me to the realization that an integrative approach is critical to scientific progress.

On a deeper level of integration, art and science enrich each other. I was recently struck by one critic's interpretation of Rembrandt's painting, Dr. Tulp's Anatomy Lesson. 2 In this view, the surgeons depicted by Rembrandt, as well as the object of their lesson, the cadaver, "will enjoy immortality as a result of scientific research in the public interest." Far-fetched, maybe, but as director of the U.S. National Science Foundation--a government agency supporting research that benefits society--I celebrate that thought.

Rembrandt himself brought a fresh eye, a new subtlety and vitality, to the genre of painting anatomy lectures. For their part, anatomy lessons held in public entertained, educated, and elevated the moral spirit. The anatomy theater itself provided a setting for discovery, rendering visible what had been hidden to the eye.

[Davidge Hall exterior]
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I would like to take us for just a moment to the other side of the Atlantic, but some two centuries later. Even then, our ability to visualize the complexity of the human body had hardly evolved much further. We see here a historic building at my home institution, the University of Maryland in Baltimore. This is an anatomy theater built in 1812. It is the oldest medical teaching facility in the Northern Hemisphere still in use.

[picture of Davidge and building interior]
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John Beale Davidge, the building's namesake, helped to found the University of Maryland's School of Medicine. The practice of medicine at the time was far from glamorous. Nor was it financially rewarding, or even safe. Human dissection was illegal and could spur public outcry. When Davidge built his first anatomical theater in Baltimore, angry youths broke in and stole a cadaver, dragging it through the city streets. Undaunted, Davidge built a more solid edifice, surrounding it with a sturdy wall. We see the interior here. Still, it was a dark, dank, and drafty setting for instruction. It smelled of oil lamps, poorly embalmed bodies, and the vapors from chemical experiments wafting up from the hall beneath.

[stairwell and barrel]
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To supply the medical school, bodies were snatched from nearby cemeteries. The bodies were hidden in barrels for transport, and carried up this circular staircase into the Anatomy Theater. The stairs also furnished an escape route for teachers and students when the public grew belligerent over human dissection.

[three pictures: Van Leeuwenhoek, "animalcule" drawing and his microscope]
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Rembrandt painted his anatomy lesson in 1632, the same year that Anthony Van Leeuwenhoek was born. My discipline of microbiology began when Van Leeuwenhoek discovered what he called "animalcules"--which we now know to be bacteria, protozoa and rotifers. Here we see his microscope and some of his drawings. He literally opened up a new world for the human eye to view, the world of microorganisms. This heralded a great leap forward in our ability to image--even gave us a glimpse of complexity. Both the microscope and the telescope, invented around the same time, framed at opposite ends a new challenge: how to interpret their images coherently, given the unfamiliar scales, both large and small.

[two Vermeer paintings: "The Astronomer" and "The Geographer"]
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In the world of painting, the Dutch artist Johannes Vermeer, also born in 1632, began to open up new ways of seeing. Here we see his two tightly linked works, "The Astronomer" and "The Geographer." It seems probable that Van Leeuwenhoek, his contemporary, was the model for these two paintings. Vermeer's depiction of the scientist striving to take the measure of heaven and earth prefigures today's awesome task: the challenge of tracing complexity.

[new composite biocomplexity image]
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From the microscopic world to the planetary scale to the expanse of the universe, our challenge today is to apply all our tools of vision, from genomics to computers to satellites, to embrace and understand complex systems. These systems range from the human body to the workings of our environment, and beyond. I use this array of images, from the small scale to the immense, to convey the connections within this complexity. Integrating the richness of viewpoints from all fields of study, and from the minute to the global, gives us a framework for science today. The perspective of complexity helps us to see into both the physical and living realms, and to probe their interconnections.

Much of modern science, up to now, has followed a reductionist approach. Following the anatomists, we have sought understanding by taking things apart into their components and putting labels on them. Now we're ready for a new perspective in the life sciences, recognizing that nothing in nature stands apart. I call this approach "biocomplexity." This is the guiding principle to tracing complex interactions in biological systems, including human beings, and relating all of this to the physical environment.

[hurricane and Louisiana, from Moppet]
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For several years, the U.S. National Science Foundation has supported biocomplexity studies, in which interdisciplinary teams examine a wide array of interactions. A good example is a study of how environmental change affects wetland communities in the Mississippi River Delta of the United States, an area that is prone to hurricanes. As the researchers note, "Over the next century, the projected change in global climate will impact sensitive ecosystems and biodiversity, particularly in coastal areas."

[iris and its ecosystem]
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The study focuses on this native iris plant, which grows in both salt and freshwater, but with very different patterns. Salt reduces plant biomass, but increases seed production. Salt also affects the plant's hormones, proteins, and aromatic compounds. Animals, too, play a role; deer consume most flowers of the salt marsh iris, but they avoid freshwater iris flowers.

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Now alligators enter the picture; when these predators take many deer, more iris flowers should survive. This should lead to an increase in the genetic diversity and seems to accelerate the adaptive evolution of the iris. The entire study, led by the University of Louisiana, combines techniques and disciplines--field experiment joined with biochemistry, molecular genetics, and predictive modeling.

[Banfield -- white "rolls" of biofilm"]
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We have seen how the environment shapes a living organism. Another study emphasizes the reverse: how an organism exerts influence on its physical environment. Led by the University of Wisconsin, this work looks at a completely different complex environment: an abandoned and flooded mine. We see biofilms here that live on the floors of the flooded tunnels. The goal of the work is to understand geomicrobiological processes from the atomic scale up to the aquifer level. Acid drainage from such mines is a severe environmental problem. At one mine being studied, workers accidentally left a shovel in the discharge; the next day half the shovel was eaten away by the acid waste.

[Banfield: blue, and yellow sulfur balls]
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We search for ways to remediate the damage in areas like these. Microorganisms, such as those in the biofilms, live in the flooded mine and play a surprising role. For one, they can clean the zinc-rich waters to a standard better than that of drinking water. At the same time, bacteria in the biofilms are depositing minerals on the tunnel floors. The yellow balls are zinc sulfide, formed in very high concentrations by the activity of microorganisms. In summary, the work sheds light on an environmental problem, while giving insights into basic science with economic benefit: we are learning how mineral ores of commercial value are formed.

[Sevilleta LTER]
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Here is another example--a study that directly links climate to the dynamics of infectious disease. In 1993, young people began dying of a mysterious respiratory disease in a remote area of Arizona and New Mexico in the western United States.

The culprit turned out to be a previously unknown hantavirus, whose vector was a rodent. Biologists, meanwhile, had been conducting long-term studies of rodents at a research site in the area called Sevilleta.

They noted a large increase in the rodent populations there. Massive rains associated with an El Nino year had fed plant growth after years of drought. That meant more food for the mice, which carry the hantavirus.

So it was the climate change that set off the disease outbreak. Now that the connections between the virus, the mouse, and climate have been made, residents can be warned in critical years.

New Mexico also has more than half the human plague cases in the United States. Recent ecological studies there have linked climate to enhanced conditions for outbreaks of bubonic plague. Predictive models now provide early warnings of environmental conditions conducive to such outbreaks.

I will now turn to a larger story--my own research. It too is a complex case of an infectious disease, cholera, linked to climate, a problem that has helped me to formulate the philosophy of biocomplexity. To set the stage, I would like to show you a brief video that takes us to Bangladesh, a country prone to cholera outbreaks, and a major site for my research. The video, please.

[Video is not available.] [Video excerpt from "MD State of Mind" TV show showing Dr. Colwell's research in Bangladesh: 2 min. 48 sec.]

[composite slide of cholera-related pictures]
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My voyage of discovery, the study of how factors combine to cause cholera, began more than 30 years ago. It is a disease that is both easy to prevent and to treat, yet remains a deadly and ever-present scourge, especially in developing nations. I gradually accumulated the evidence that a disease like cholera does not exist in a vacuum. In endemic regions, cholera appears seasonally. This is caused by environmental factors that alter the populations of the larger host organism for cholera, the copepod, which we saw in the video. Climate, seasonal weather changes, and seasonal changes in ocean currents all affect the growth of copepods. Add in the 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 can even look at molecular factors related to the toxin genes in some vibrios.

My team now comprises collaborators working in the coastal areas of Southeast Asia; others in Central and South America, where cholera reemerged in the last decade; and researchers from the National Aeronautics and Space Administration (NASA). All are needed to elucidate ancient questions--such as from where does cholera arise, how does it travel, and what can be done to prevent it?

[Cholera statistics, 1999: WHO]
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The latest numbers of cholera cases from the World Health Organization are incomplete figures for 1999: 254,310 cases and almost 10,000 deaths. These don't include Bangladesh, Pakistan, both North and South Korea, and several other countries, whose aggregate numbers may equal those for the rest of the world, shown in this slide.

[Table: worldwide cholera, 1991]
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To give an idea of possible worldwide totals, especially in years of epidemics, a representative year is 1991, when over 200,000 cases were counted in three months in Bangladesh alone. From August through October, a thousand cholera victims entered the cholera hospital in Dhaka, Bangladesh every day.

[Map: Global spread of cholera, 1961-91]
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The map summarizes the epidemic years of the current pandemic, the seventh one, which began in the Celebes in 1961. Many factors still combine to create outbreaks--poor sanitation, poverty, lack of clean water, wars, and economic displacement. People who live near water, especially near the coast, are most at risk.

[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. 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. In more recent times, cholera has affected human populations and cultures in as many as eight major pandemics, with the first documented occurrence in 1817 around Persia.

[John Snow map: cholera cases in London, 1854]
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By the mid-1800s, British physician John Snow realized that cholera was spread through drinking water contaminated with sewage. He plotted deaths from cholera in a London neighborhood, and noted that those who were ill had drunk water from a particular pump. This was the first epidemiological study ever done.

[Old cartoon: pump and death]
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Snow removed the handle of the water pump in the affected area of London, and the epidemic abated. Italian scientist Filippo Pacini first described the cholera bacterium in 1854. However, he was ignored because at that time the germ theory of disease was not yet accepted.

(His slide preparations and microscope records are on display today at the University of Florence in Italy. Almost a century-and-a-half later we can still see the cholera bacteria stained by Pacini.) German physician Robert Koch redefined the bacterium as the causative agent of cholera and isolated what he called "V. comma" --because of its curved shape--in pure culture in 1883.

[intestinal chemistry diagram]
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It wasn't until 1959, more than 140 years after the beginning of the first pandemic, that an Indian scientist, Sambhunath De, discovered and described the Vibrio toxin. The production of this toxin by the bacterium changes the permeability of the cell membrane in the intestine of infected individuals, enabling secretion of massive amounts of water and electrolytes into the lumen of the intestine. If these fluids and electrolytes are not replaced rapidly, death follows.

Although not all members of the genus Vibrio produce toxins, many do. Twelve of the 30 known species of this bacterial genus cause human diseases.

[Graph: V. vulnificus-tainted shellfish deaths and illness]
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One of these vibrios, Vibrio vulnificus, can cause gastrointestinal infection in those who eat raw shellfish and wound-infection in those who handle the mollusks or swim in seawater where the organism is abundant. Other Vibrio species cause disease in animals.

[Chesapeake Bay cholera sampling sites]
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In the 1970s, my colleagues and I realized that the ocean itself is a reservoir for V. cholerae, when we identified the organism in water samples from the Chesapeake Bay off the coast of Maryland and Delaware. Earlier detection methods for V. cholerae were developed strictly for testing clinical samples. In environmental samples, V. cholerae is more difficult to detect. The organisms may be more dispersed in the water and they may be dormant--not actively metabolizing.

What do we know about Vibrio cholerae--this organism that is so destructive of human lives and of the economies of nations? The family, Vibrionaceae, includes brethren that are completely benign and indeed, necessary to the recycling of matter in the environment. Many species of Vibrio, in addition to V. cholerae, live in rivers, estuaries, and brackish water. But culture results do not reflect the actual numbers of microorganisms present in an area, because we cannot always grow these vibrios in the laboratory, even though we can detect their presence using molecular methods.

[copepod close-up]
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Here we see a copepod close up--the minute relative of shrimp which forms part of the zooplankton populations in aquatic habitats. This microscopic animal lives in salt or brackish waters, including rivers and ponds, and travels with currents and tides. Copepods harbor both dormant, nutrient-deprived, and culturable vibrio. The bacteria can survive as an inactive--dormant but still infectious--spore-like form in the guts and on the surfaces of the copepods in between the epidemics. The Vibrio can be cultured somewhat more easily in the summer months.

[graph: V. cholerae numbers on copepods]
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In fact, a single copepod can harbor as many as 104 Vibrio cholerae cells. Most recently, we have used the latest genetic techniques--polymerase chain reaction and gene probes--to detect Vibrio directly from environmental samples, confirming the earlier immunofluorescent detection results.

[Small chromosome]
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In 2000, the genomes of the two chromosomes possessed by V. cholerae were sequenced. The discovery of two chromosomes was interesting, because bacteria were presumed to have a single chromosome. Both chromosomes are necessary for metabolism and replication.

[Large chromosome]
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The toxin genes reside on the large chromosome. The sequencing data confirm that V. cholerae is a versatile organism, able to live in several habitat types, as well as to infect the human gastrointestinal tract.

As human beings, we are attuned to the changing seasons on land, but seasonal changes in the ocean, less obvious to us, are just as dramatic. I would like to show you a video with satellite imagery of plant production in the ocean changing through the seasons. We will see changes in phytoplankton--the microscopic plants that are the base of the ocean food chain. Blue and green colors show a greater concentration of chlorophyll, or plants, while purple shows less chlorophyll.

In keeping with the spirit of today's occasion, we will also be hearing part of a musical piece called "The Climate Symphony." American composer Marty Quinn created this piece based on actual data on climate change over centuries. Specifically, the data record the main cycles of atmospheric circulation in response to the growth and decay of ice sheets. Musical instruments denote different components such as the earth's wobble, ocean circulation, and even volcanic activity. Of course, the changes actually take decades or millennia, and the pace of the music is obviously much faster. The video, please.

[Video is not available.] [Video: oceanic plant production, with music; 33 sec.]

[Monitoring temporal patterns of cholera...]
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What is the relevance of all this to cholera? Our most recent studies have used remote sensing imagery to gather data on sea surface temperature and sea surface height, discovering in the process a clear correlation of the temperature periodicity to be linked to the periodicity of cholera outbreaks in Bangladesh and in South America. Simply stated, we have found a positive correlation between increased sea surface temperature and sea surface height and subsequent outbreaks of cholera.

Heating of surface waters, especially off a tropical or subtropical coast, results in an increase in phytoplankton. Through remote sensing, we can now determine when that bloom is occurring. The phytoplankton, in turn, provide food for zooplankton, which then increase. Zooplankton include the copepods that host the cholera bacteria.

[cholera outbreaks, SST and SSH]
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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. The following video of satellite imagery of the Bay of Bengal will show how sea surface temperature changes with the seasons over the year.

We'll see the waters warm in spring--denoted by green and yellow, even red colors, and then the monsoon cooling. Then, the ocean warms again in fall, with some red visible at the mouth of the Ganges River. This cycle repeats every year. The video, please.

[Video is not available.] [Digital video of SST in Bay of Bengal: 55 sec.]

[Sea Surface Temperature Bay of Bengal]
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[Cholera in Latin America]
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Let's move to the Western Hemisphere. The sea surface temperature there is influenced by the El Nino-Southern Oscillation, or "ENSO" for short. That is the anomalous warming of the ocean surface that occurs periodically off the west coast of South America. The oceanic mechanism sets off changes in the atmosphere in the Pacific Ocean and beyond.

After a century without occurrence of cholera, Vibrio cholerae invaded the Western Hemisphere in 1991, by way of Peru. This was an El Nino year which produced conditions conducive to a cholera outbreak.

We'll now see two videos side-by-side, showing sea temperature off South America in two contrasting years: one with an El Nino and one without.

On the right we'll see sea surface temperature fluctuating over an El Nino year, 1997-98. On the left, we'll see temperature a year without El Nino, 1995-96. The comparison clearly illustrates the signature of El Nino. Look especially at the sea off Peru and Mexico, near the equator, and see how that differs between the two years, especially in July through December. The videos, please.

[Videos are not available.] [pair of digital videos of SST off South America in contrasting years: 55 sec.]

[Sea Surface Temperature South America]
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[image: ship ballast release]
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There is yet another dimension to the spread of cholera. We recently published a brief communication in the journal Nature on how ships can transport pathogens in their ballast tanks, based on our measurements of the cholera bacteria in ballast water. It turns out that ballast water harbors significantly large numbers of copepods, because copepods don't require sunlight for growth. They are hardy creatures, surviving well in the hold of a ship during a long transatlantic voyage.

[Zebra mussels]
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Not only can such introductions impair human health, but they can also imperil aquatic ecosystems. We learned this lesson, sadly, in North America, when zebra mussels were introduced into the St. Lawrence River and the Great Lakes through ships' ballast water. We see how mussels can encrust the interior of pipes.

Similarly, some cholera outbreaks associated with shellfish may well have originated with ballast water, contaminated with V. cholerae, being discharged by a ship in a coastal or estuarine area near a shellfish bed. The discharged ballast could have concentrated the bacteria over filter-feeding shellfish beds on the estuary floor, as the shellfish eat the bacteria.

[sari cloth water filtering]
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Although the explanation of cholera outbreaks is global in scale and includes many factors, the solutions can be surprisingly simple--and they can be implemented on a very local scale. Cholera transmission is easily controlled by providing people with clean, uncontaminated water for drinking and bathing. As we saw in the film excerpt from Bangladesh, even at the most basic level, we have found that straining water through several layers of sari cloth may be enough to prevent ingestion of infectious levels of V. cholerae.

[cholera cases: sari vs. non-sari]
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A sari cloth, readily available even in the poorest household, can be folded eight to ten times. This creates a 20 ( mesh filter, as we determined by electron microscopy. Here we see the results of testing sari cloth as a filter to remove plankton. Its use reduces the number of cholera cases by half or more. 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.

Our work has touched upon remote sensing, biodiversity, and even genomics, since we were partners in the sequencing of the Vibrio cholerae genome. As we work with households in cholera-prone areas, our research reaches into the realm of social science as well.

We expect that relationships between ocean salinity, chlorophyll content, and cholera outbreaks will be found. We will be able to track ocean currents and how they affect plankton associated with the bacteria, ultimately giving us the ability to predict outbreaks of the disease on a global scale.

We see that the more we understand the ecology of a pathogen, the better we will be able to predict the interactions of climate and human health.

We need the perspective of complexity to grasp the working of systems, whether on the scale of our planet, our climate, or our own bodies. I would like to return, as I close, to where this lecture began--back to the complex system of the human body.

[Visible Human Project]
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Rembrandt's canvas reminds us of the revolutionary journey that medicine has taken since the era of crude dissection. Today, we have the Visible Human--really two humans, male and female. This digital library has images from cryosectioning, from computerized tomography, and from magnetic resonance imaging of cadavers--taken at one-millimeter intervals. Again, we have an example of reductionism revisited to yield an understanding of the complex whole. These sets will serve as reference points to study human anatomy. Scientists, doctors, teachers, mathematicians, and, of course, artists in 43 countries are now using this international resource.

On the grander scale, satellites display a comprehensive view across space and time, computers enable fantastic visualization and handling of massive amounts of data, and we come to the threshold of prediction for complex systems, whether diagnosing and treating disease or linking human health to our environment.

To complete our journey back to where we began, I would like to share with you one last video. It connects back in a metaphorical way to our predecessors' attempts to see inside our own bodies. This is an excerpt from a new, large-format film called "The Human Body." The National Science Foundation supported the making of this film, as part of our mission to promote science and technical literacy. The film premiered just last month in Baltimore and in London. It is a BBC/Discovery Production in association with the Maryland Science Center and the Science Museum of London. The spectacular images we will see draw from research across many fields, and from this composite comes a renewal of wonder at what it means to be alive. The film illustrates the breathtaking ability to image ourselves. First we travel inside the human ear, then inside the lungs, and finally, to the engine of the body--inside the beating heart. Let us begin the journey.

[Video is not available.] [The Human Body Imax film video excerpt--3:48 with video version of still montage; still montage remains on screen for duration of talk]

Aristotle said that the soul never thinks without an image. Today, science and engineering have brought new ways of seeing to every discipline of research, from microbiology to medicine and beyond. We are now able to see at scales from the Lilliputian to the immense, to capture the complexity of our world, and even to simulate what we cannot directly see. These abilities stretch our very definition of what it means "to see."

Science is but one port in this journey, and I choose my closing words from another harbor: the realm of poetry. Many of us in science are drawn to the words that end the poem of T.S. Eliot called "The Four Quartets: "We shall not cease from exploration/ and at the end of all our exploring/ Will be to arrive where we started/ and know the place for the first time." The voyage of discovery to ever-deeper levels of complexity will never end. Thank you.

1. E.O. Wilson, Consilience. Back to speech.

2. Herbert Scherer, "Rembrandt's 'Dr. Tulp's Anatomy Lesson,'" Minnesota Medicine, Nov. 1990, Vol. 73. Back to speech.



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