Genetic Blueprint of Cholera Bacterium Determined
A century and a half after a British doctor figured out that the dread disease cholera was caused by drinking contaminated water, the genetic blueprint of the bacterium responsible for the sickness--which afflicts several hundred thousand people each year--has been fully determined.
With the world in the midst of a cholera pandemic, scientists expressed surprise and excitement at the secrets revealed by the effort, and optimism that the information will lead to a better understanding of how the microbe lives and spreads disease.
The finding should also aid in efforts to fight the comma-shaped bug--by, for instance, developing better vaccines.
The genome of Vibrio cholerae, now laid bare, also illustrates principles about how microbes evolve: a process in which chunks of DNA are promiscuously shuttled back and forth between wildly different germs, through bacterial sex or by viruses.
Scientists from three institutions--the Institute for Genome Research, the University of Maryland and Harvard Medical School--participated in the V. cholerae genome project. The study, which was led by genome institute scientist John F. Heidelberg, is reported today in the journal Nature. But scientists have been mining the data from the World Wide Web for some time.
“For people studying this organism, it’s just an enormous resource,” said Dr. Matthew K. Waldor, assistant professor of medicine at the Tufts New England Medical Center in Boston. “It’s the complete genetic information--the entire coding capacity of the organism.”
Dr. David Brandling-Bennett, deputy director of the Pan American Health Organization, said, “Our ability to decipher and then understand the genomes of pathogens like these is going to have a much more immediate impact on human health than the human genome project.”
Cholera is a bacterial infection of the small bowel that causes violent diarrhea and massive loss of fluid and salts--and often rapid death, if not treated.
Rehydration therapy--in which fluids and electrolytes are given orally or intravenously--usually results in rapid recovery. But malnutrition lowers resistance, and epidemics can flare up suddenly and cause high casualties if help doesn’t come in time. During one month in 1994, 23,800 people died of cholera in a refugee camp in Zaire.
The scourge has probably afflicted humanity for millenniums. But it was only in the 19th century that six successive waves of the disease swept through the world in pandemics, sparking panic and prayer in the communities it struck. Increased human travel--for trade purposes and even religious pilgrimages--helped carry the bug on its way.
A seventh pandemic, which began in 1961 in Indonesia, reached the shores of South America in 1991. It is still in full force after nearly 40 years.
This pandemic is caused by a new variant of the germ, and (for reasons scientists don’t understand) is persisting longer than previous ones. According to the World Health Organization, there were 293,121 cases and 10,586 deaths in 1998.
In the United States cholera cases are very rare and come from the occasional ingestion of contaminated shellfish.
It was only in 1854 that the main route for cholera infection was discovered. Dr. John Snow, a British doctor, traced a cholera outbreak in central London to a pump delivering filthy, feces-contaminated river water. He persuaded local authorities to remove the pump’s handle.
And in 1883, German physician Robert Koch linked the disease to a germ he christened “Kommabacillus,” for its shape.
The determination to fight cholera was the main driving force behind the development of modern public health surveillance and modern water and sewage treatment systems in the developed world.
Much Research Remains to Be Done
Today, with the solving of V. cholerae’s DNA “sequence” (the precise order of the building blocks known as A, T, C and G), scientists can probe the cholera bug with a precision that would have boggled the minds of 19th century physicians.
And they are intrigued by some of the features that they have found.
Half of the bacterium’s nearly 4,000 genes are largely unrecognizable: scientists don’t know what their jobs are.
“We’re not going to understand this organism for many, many years to come, that’s for sure,” said John J. Mekalanos, a coauthor of the paper and professor and chairman of the department of microbiology and molecular genetics at Harvard Medical School.
And the germ contains many genes to help it sense different nutrients and shuttle them into the cell. This may be why it can live in anything from briny water to bellies of marine plankton and the human gut.
V. cholerae contains two unusual circles of DNA instead of a large, single piece. Since two small pieces divide faster than one large one, this might help the bug reproduce faster.
The V. cholerae genome also bears relics of past encounters with other creatures that have helped make the microbe what it is today.
For instance, the genes for the cholera toxin--which causes the horrendous fluid loss--were the gift of a virus that entered V. cholerae long ago, donated by some creature unknown.
Genes within the cholera microbe that code for tiny hairs that are needed for invading human guts also seem to have come from elsewhere--perhaps another microbe that V. cholerae once encountered sexually.
The whole second chromosome, in fact, may have been captured from another critter long ago.
“It’s becoming increasingly clear that this kind of ‘horizontal gene flux’ is an important force in shaping bacterial evolution,” said Waldor, whose lab first reported the cholera toxin-virus link.
Now scientists are undertaking new experiments to better understand V. cholerae.
Rita R. Colwell, director of the National Science Foundation and coauthor of the genome paper, was the first to report that V. cholerae also lives naturally in marine water. She plans to study how the microbe can do this, and to further explore her theory that marine plankton--not humans--is the bug’s principal host.
In fact, Colwell says, it’s even possible that the same cholera toxin that proves so deadly to a human may have evolved for a quite innocuous purpose: to help the microbe deal with the salt in its marine environment.
Scientists also want to understand more about what the bug eats, so they can figure out a way to design a drug that chokes off its ability to derive energy. They want to know what events trigger pandemics and epidemics--and pinpoint other genes that contribute to the symptoms of the disease.
And then there is the quest for a better vaccine.
Existing vaccines for cholera have limitations. For instance, the immunity they confer lasts just a couple of years, and they are only about 60% to 80% effective.
It’s possible, scientists say, that exploring the cholera genome will offer clues to help make a vaccine that is more effective and lasts longer.
“I certainly share the hope that that will come to pass,” said Dr. Eric Mintz, medical epidemiologist at the Centers for Disease Control and Prevention in Atlanta.
But it won’t happen overnight, he said--and every effort, in the meantime, should continue to be made to secure clean drinking water and proper disposal of sewage.
