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Hiding from the World
Scientists Sequence the Elusive Whipple Genome
  
By
Edward R. Winstead



Featured Article.

The microbe that causes Whipple’s disease has been nothing but trouble. Wily and elusive, it can live undetected in the body for decades and then, without warning, cause a fatal illness. What’s more, until recently scientists have not been able to study the pathogen because it all but refuses to grow in the laboratory.

Yet this deadly creature may ultimately contribute something to society, or at least to science. The microbe’s genome has just been sequenced. The information will be used to study Whipple’s disease, and it may also help researchers discover ways to cultivate microbes that are difficult to grow in the laboratory.


Image of biopsy from a patient with Whipple's disease.

Most microbes on the planet cannot be cultivated and are therefore difficult to study. In 2000, French researchers succeeded for the first time in growing the Whipple’s disease pathogen, Tropheryma whipplei, in the laboratory. Now, with the genome sequence in hand, the field is learning about a pathogen that has been an enigma for decades.

“So little was known about the organism previously that almost everything we’ve learned from the genome has been a surprise,” says Stephen D. Bentley of The Wellcome Trust Sanger Institute in Cambridge, where the sequencing was done.

The first surprise was the size of the genome. The organism has one of the smallest genomes of known bacteria. And the genome is missing many genes found in other bacteria, including some for nutrients and amino acids thought to be essential. The microbe may rely on its host for these.

Perhaps the biggest discovery from genome project was a new family of proteins on the surface of the bacterium that can change over time. By varying the appearance of these surface proteins, the microbe may be able to travel undetected throughout the body.

“This may be why the microbe can cause chronic infections over many years and still not be recognized and attacked by the human immune system,” says Matthias Maiwald of Stanford University School of Medicine in California, who led the effort to grow the pathogen for the genome project.


Title page of the first report, in 1907, of the disease by George Hoyt Whipple. View larger

Other microbes have been known to alter their proteins. What’s novel about the T. whipplei proteins, the researchers say, is how they are altered. According to their theory, the genes for surface proteins can incorporate DNA from elsewhere in the genome, thereby altering the proteins.

The genome sequence revealed that these genes are large, taking up a significant percentage of the genome. Indeed, the microbe devotes a great deal of energy to proteins that are on the front line between it and the host.

“Here we have an organism with a huge amount of its genome devoted to surface structures, and these proteins have built-in mechanisms that allow them to change over time,” says Maiwald.

Despite how rare it is, Whipple’s disease has been included in medical textbooks ever since 1907, when the first case was reported by the American pathologist George H. Whipple. Today, about one case occurs per million people each year in Europe.

“The unusual features of this organism have fascinated clinicians and given it notoriety among the world of bacteriology,” says David A. Relman of Stanford University School of Medicine in California, who co-led the sequencing project.

“The unusual features are: what makes it so difficult to grow the microbe, the fact that it elicits an unusual inflammatory response that does not cure the infection, and its unusual cell wall.”


False-color image of Tropheryma whipplei.

The pathogen’s cell wall is a barrier seemingly designed to confuse the human immune system. The wall is thick and has an outer membrane apparently appropriated from human cells.

Many physicians learn about Whipple’s disease because it has numerous symptoms and manifestations. It can cause arthritis, intestinal disorders, and dementia. Physicians often want to rule out Whipple’s disease when diagnosing these more common disorders.

Why the disease is rare is not known. One theory says that T. whipplei is a rare organism. Another says that T. whipplei lives in the human gut, but only causes problems when there are certain deficiencies in the immune system.

Men get the disease eight times more often than women, and it mostly affects white males of middle age. The disease is thought to occur at roughly the same rate in Europe and the United States; but it is less common in Africa and Asia. Only one Asian—a Japanese man—is known to have developed the disease.

“The disease occurs rarely in African-Americans,” says Maiwald, adding that there may be a genetic predisposition for the disease among certain racial groups.


George H. Whipple (1878 - 1976) was the first American to receive the Nobel Prize in Medicine and Physiology, winning in 1934 for his research on anemia.

Whipple’s disease disproportionately affects people who work outside, a survey of 700 reported cases worldwide found in the 1980s. More farmers and carpenters got the disease than members of any other profession. As with so much about the disease, no one knows why.

Obtaining sufficient DNA for the genome project was a major accomplishment. It took fifteen months for the researchers to grow the bacterium using human cells in a culture system similar to one developed by the French group in 2000.

Here's why: the bacterium took four days to do one cell division and reproduce. By comparison, the leprosy bacterium Mycobacterium leprae takes approximately twelve days, while an ordinary strain of E. coli takes about 20 minutes and generates an entire culture overnight.

“The kinds of things we learn about the growth requirements for this pathogen may help us characterize other human pathogens,” says Relman.

“This is a very gratifying point in the research on Whipple’s disease for me personally,” Relman continues. “I’ve been staring at this organism for thirteen years; I’m amazed at how much more we now know about an organism we knew so little about a decade ago. And yet it remains an enigma.”

For more information visit Whipple´s Disease Online

See related GNN art gallery
»The Whipple Bacillus

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Bentley, S.D. et al. Sequencing and analysis of the genome of the Whipple's disease bacterium Tropheryma whipplei. Lancet 361, 637-644 (February 22, 2003).
 
Schaffner, A. and Schneemann, M. Whipple's disease--from enigma to genomics. Lancet 361, 632 (February 22, 2003).
 

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