Science in the time of cholera

What cholera can teach us about climate change


Our planet is sick. Changes in the climate harm the Earth’s health. But what about our health?

Tomer Hanuka

Infectious disease expert Gary Schoolnik, MD, and an international team of scientists are honing a model that will offer at least part of an answer. Ultimately it could forecast how global climate change will influence the spread of diseases. Along the way it could save millions of lives by guiding public health officials in preparing for an outbreak or preventing one.

The teams are monitoring the impact of mankind’s disturbances by scrutinizing the life cycle of the bacterium Vibrio cholerae, which sickens hundreds of thousands annually with cholera.

Global climate change and its effect on increasing seawater temperature and monsoon rains stimulates the growth of algae and the small algal-feeding crustaceans that harbor the cholera microbe. Together, these ecological changes lead to more intense cholera outbreaks. “Warming temperatures will affect the aquatic habitats where these infectious agents reside, increasing the probability that they will emerge from these reservoirs and cause disease,” says Schoolnik, professor of medicine and of microbiology and immunology, and senior fellow at Stanford’s Woods Institute for the Environment.

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Cholera causes disease primarily in developing countries that lack adequate sanitation and clean drinking water. While treating the disease is simple and inexpensive, in areas lacking resources the fatality rate hovers around 10 percent, killing hundreds of thousands of people. Victims die from a massive effusion of watery diarrhea that depletes them of fluid and electrolytes.

Cholera epidemics are explosive and dramatic, rapidly progressing from a local problem to a regional and sometimes global outbreak. Currently the world is in the midst of a pandemic that started in Indonesia in 1961 and spread rapidly in Asia, Europe and Africa, reaching South America in 1991.

Though the disease has afflicted humans for centuries — a disease similar to cholera was recorded in Sanskrit writings in what is now India in 500 B.C. — the mechanism that sets off sudden outbreaks has been a mystery. As a result, efforts to predict outbreaks and intervene have met with little success.

Real hope arose in the 1970s when microbiologist Rita Colwell, PhD, now a professor at the University of Maryland and at the Johns Hopkins Bloomberg School of Public Health, discovered that the disease-causing bacteria live in oceans, rivers and estuaries between outbreaks. Schoolnik notes that Colwell realized decades ago that factors affecting V. cholerae’s aquatic environment — water temperature and depth, rainfall, dissolved chemicals and algae growth — all have a direct impact on outbreaks. “She was the first to find the voice for the general idea of vibrio being an organism whose epidemiology is reflective of climate change,” he says.

All hands on deck

It’s a huge question: How can humans flourish on Earth while protecting and restoring the planet for generations to come? The search for an answer is what drives Stanford’s new Woods Institute for the Environment.

In 2004 Stanford launched a campuswide initiative to promote an environmentally sustainable world. Then last year, Stanford University alumnus Ward W. Woods, '64, and his wife, Priscilla, committed $30 million to the fledgling Stanford Institute for the Environment, which was renamed the Woods Institute for the Environment. A hub for the school’s environmental education, research and problem-solving efforts, the institute will be housed in the Environment and Energy Building slated to open late this year.

Directed by law professor Barton H. “Buzz” Thompson Jr., JD, and engineering professor Jeffrey Koseff, PhD, the institute pulls together more than 200 faculty and researchers from all seven schools on campus. They teach and conduct research on topics ranging from quantifying the true value of nature (how much does a honeybee contribute to a Costa Rican coffee-growing economy?) to determining the worldwide population of humpback whales before the onset of commercial whaling (was it the widely accepted estimate of 100,000 or was it 10 times larger, as DNA analysis suggests?)

The institute strives to help Stanford researchers break out of the ivory tower. Several institute projects bring Stanford scientists together with outside organizations, among them the aforementioned effort to quantify nature’s economic import, the Natural Capital Project — a joint effort of Stanford faculty, the World Wildlife Fund and The Nature Conservancy. The institute’s leadership program takes an even more direct approach, training scientists to interact effectively with policymakers and the media.

The institute also supports research projects unlikely to receive funds through traditional sources. The most recent round, announced in May 2006, awarded five two-year grants totaling $670,024, including two with medical bents. One aims to improve indoor air quality in Bangladesh, where use of dung- and brush-burning stoves seems to contribute to respiratory infections. Another explores the connection between water and childhood survival in Mozambique, where roughly 90 children die each day, mostly from the water-related diseases diarrhea and malaria.

“It’s great to help one sick patient at a time,” says Gary Schoolnik, MD, professor of medicine and co-leader of the Mozambique project. “But if you can understand a new fundamental, you can help a whole population of people.” — Rosanne Spector

Colwell continued investigating environmental fluctuations that affect cholera and in the 1980s found that while V. cholerae can live freely in water, it also attaches to tiny crustaceans — microscopic shrimp-like animals called copepods — that provide a natural refuge. The ability of the organism to hunker down on the ubiquitous copepods between outbreaks strongly suggests that cholera will probably never be eradicable, says Colwell, who went on to direct the National Science Foundation from 1998 until 2004.

“The copepod’s gut is filled almost entirely of vibrio, just as we have E. coli in our guts as mammals,” she says. Studies from her group indicate that a single copepod can carry 10,000, possibly even 100,000, V. cholerae bacteria.

In places where cholera is endemic, such as around the Bay of Bengal, unfiltered and untreated water contains about a half-dozen copepods per liter most of the year. But hotter weather warms the water and triggers a burst in the growth of algae, which is the copepod’s food source. Four to six weeks later the copepod bloom occurs, resulting in an increased concentration of up to 100 per liter of water.

“That gets you to the infective dose to cause cholera,” says Colwell. The initial cases of cholera that emerge trigger the massive amounts of diarrhea that lead to the person-to-person chain of infection seen during an outbreak.

Recently Schoolnik’s group showed that the chitin-containing exoskeletons of copepods not only serve as a source of nutrients for V. cholerae, but can also stimulate its capacity to harvest genes from the environment. “As a result, climate change can drive the evolution of the microbe,” says Schoolnik.

Scientists see a link between climate change and the increasing magnitude of cholera outbreaks. Since the late 1970s, along with the planet getting warmer overall, there has been a tendency toward periodic dramatic ocean temperature warming. Because V. cholerae thrives in warm water, it is particularly sensitive to changes in climate patterns. And indeed, cholera outbreaks have also increased since the 1970s.

Colwell’s group made the leap of using remote sensing data to forecast outbreaks. “What we have been able to do with satellite imagery is predict when and how intense the epidemics will be using environmental data — chlorophyll, sea surface temperature, sea surface height — all of which is monitored on a daily basis by satellites,” says Colwell.

Still, many details must be resolved before scientists can routinely predict cholera outbreaks globally. Part of the problem, says Schoolnik, is that so many variables change at once. “During the last three decades, increasing algal blooms have occurred and these have been associated with exacerbation of cholera outbreaks,” he says. “But many other changes have occurred at exactly the same time — increased flooding, increased population density, increased chemical fertilizer use.”

Adding to the complexity, V. cholerae itself can change. Deadly outbreaks of cholera in India and Bangladesh after 1992 were caused by a strain of cholera that had not previously been known to cause epidemics. This strain had picked up genes that allowed it to infect people previously immune to prior strains of the cholera bacteria, an experiment of nature recently re-created in the laboratory by Schoolnik’s group.

To tease apart the contribution of all the different changes occurring simultaneously, research groups largely at Stanford, the University of Maryland, Johns Hopkins and the National Oceanic & Atmospheric Administration are working with scientists in Bangladesh to refine a disease prediction model — a computational method that will use real-time climate, ecological and epidemiological data to accurately calculate when and where a cholera outbreak will occur and how severe it will be.

Several Stanford projects aim to flesh out this model. In one of these, Schoolnik is working with agricultural economists Rosamond Naylor, PhD, and Walter Falcon, PhD, to study the association between fertilizer use, nitrogen-rich runoff, algal blooms and cholera outbreaks in Bangladesh. In another, Schoolnik is working with former Stanford postdoctoral scholar Fitnat Yildiz, PhD (now on the faculty at UC-Santa Cruz), bioinformatics expert Peter Karp, PhD, and engineer Alfred Spormann, PhD, to learn which genes are turned on at different stages in V. cholerae’s life cycle, what those genes accomplish and how physical conditions in the bacteria’s natural environment influence gene expression. To further understand the impact that V. cholerae gene expression has on its ability to cause disease, a team at Stanford is monitoring changes in its coastal waters habitat using an optical detection method. Engineers Alexandria Boehm, PhD, and Craig Criddle, PhD, molecular imaging expert Chris Contag, PhD, and Schoolnik are leading this project.

“What we envision is predictive power,” says Criddle.

A heads-up on where cholera outbreak conditions are brewing would help public health officials get therapies to where they’re needed — and possibly even use preventive measures such as water filtration to nip them in the bud.

A predictive method will come none too soon for those directly affected by the disease. “If the prediction of cholera outbreaks can be done and an early warning system can be developed, then thousands of lives and million of dollars can be saved,” says Sirajul Islam, PhD, head of the environmental microbiology laboratory at the International Centre for Diarrahoeal Disease Research Bangladesh. Islam, one of Colwell and Schoolnik’s key collaborators, is preparing a grant with Schoolnik to use their model to predict cholera outbreaks.

In addition to predictive power, that understanding is permitting scientists to begin spelling out in detail the widespread health consequences of climate change.

“This model in all its complexity translates to other infectious diseases for which the United States is under a definite direct threat,” says Schoolnik. A consequence of increasing average temperatures is the northward journey of new threats from insects that normally reside in Mexico and the Caribbean. Mosquitoes carrying dengue and malaria — both debilitating and potentially fatal diseases — are predicted to move progressively to higher latitudes as global temperatures increase, he says.

Much as an elevated body temperature indicates disease in a person, the planet exhibits signs that it’s feeling run-down. And what’s bad for the planet will turn out to be bad for us. Perhaps the cholera model will offer a means of taking the planet’s vital signs — and point to a treatment.

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