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 How and when did you first start doing research on cholera?

I was an undergraduate at UCLA in the early 1970s, and my first job in a laboratory was actually in a cholera lab. That's what I've been doing ever since. So I did some research as an undergraduate on cholera, and as a graduate student—I got my Ph.D. in 1978—and then I came to Harvard to do a post-doc, because the right thing to do back then was to do a post-doc at Harvard so you could then get a job back on the west coast, but I stayed here. So I've been doing cholera research for my whole career, for more than 30 years. This has been my life, to try to understand this organism.

 Your most-cited paper in our analysis, published in August 2000 in Nature, was the sequencing of the cholera genome (Heidelberg JF, et al., "DNA sequence of both chromosomes of the cholera pathogen Vibrio cholerae," 406[6795]: 477-83). That was early in the game for whole-genome sequencing. How did that come about?

Well, in part that came about through a variety of personal contacts with Craig Venter (see also), who was leading The Institute for Genomic Research (TIGR). Rita Colwell, a cholera research colleague, was a board member of TIGR at the time. Vibrio cholerae was on the short list of pathogens to sequence after TIGR had its huge splash with the first bacterial genome—Haemophilus influenzae. I got involved in writing a grant proposal to sequence the genome of V. cholerae with Claire Frazer, John Heidelberg, and other colleagues at TIGR, NIH funded it, and they did a wonderful job getting it done.

 What did you learn from the sequence?

"...as we get closer and closer to strains of the organism that have emerged as human pathogens, they become less diverse and more clonal, virtually identical."

In the end, when the genome came out, there really wasn't a lot to say at that moment. No "aha!" moments came out of the genome. Really, decades of research by many different laboratories had genetically torn apart this organism pretty thoroughly. So when the genome of this strain was sequenced, it didn't reveal any new answers for unsolved big problems.  

It did provide a roadmap for doing many more studies to find genetic answers to questions that are still outstanding. Those required still more science, basic laboratory investigation, the development of assays framed specifically to the questions being asked, and then either mutational or genetic analysis to give answers to those questions. Still, my general feeling is that genomics is a tool, a starting point for studying model organisms, that now is absolutely essential.

 So why no "aha!" moments?

Recall that back in 2000 when that study was published, fully 60% of identifiable genes in the organism had no identifiable function. Since then, we have incrementally moved closer and closer to 50%. We're still looking at an organism in which the majority of genes don't have an identifiable function. We may have a motif that says, for instance, that this gene is an oxidase gene, but we don't know what it's oxidizing.

So the remarkable thing is that the genome is only now really beginning to pay off. For example, we used the genome to build a DNA chip that provided some early conclusions about the evolution of this organism, and more recently to construct mutations in every one of its genes. More recently, Rita Colwell and various other investigators, including my collaborators, have used comparative genomic information about the cholera organism to establish some conclusions about epidemiology, about the origin of pathogenic species, about the relatedness of various outbreak strains, etc.

The field now knows that "pure" environmental strains (ones not associated with a human cholera outbreak) are closely related in evolutionary terms to clinical isolates—maybe 99% similar. However, there are differences—particularly the presence of virulence genes in clinical isolates that are absent in pure environmental isolates. And clinical isolates can be 99.999% identical to each other—clonal is the word.

We recognize now that this organism does have a different life, if you will. There are many forms of this organism free-living in the environment, and the genome has that signature. There are clusters of genes that look like they're involved in the metabolism of substrates that are only present in the environment. We can see all that in the history of the genes. 

John Mekalanos next to Dr. Shah Faruque, his collaborator on cholera studies at the International Center for Diarrhea Disease Research, Dhaka, Bangladesh and other members of his research group.

However, as we get closer and closer to strains of the organism that have emerged as human pathogens, they become less diverse and more clonal, virtually identical. We believe this reflects human amplification through disease. Most of the genes that allow the organism to cause disease indeed have the signature of having been recently acquired by the organism.

So environmental strains can become pathogens by gene acquisition but once they take that leap, then they become more and more dependent on that lifestyle and seldom re-establish themselves as free-living in the environment. I think that if that was the case, we would see environmental isolates that were 99.999% identical to clinical isolates but that lacked virulence genes like other environmental isolates. We don’t see that so they are horses of a different color.

If we look at the pathogen from Haiti, for instance, and look at a V. cholerae isolated from nearby US Gulf Coast water in 1980, we will see probably 200 to 300 genes that the pathogen has and the non-pathogen doesn't out of a total of nearly 4 million genes. About a third of those pathogen genes are causing very significant characteristics in the organism that are associated with disease. But the other two-thirds of the pathogen-associated genes we don't understand. My guess is they are needed for the lifestyle change—the need to be replicated in humans and transmitted to another human.

We're still in the process of trying to understand how the pathogen evolves, and understand which organisms we're dealing with; one that is environmentally very fit but a poor human pathogen, or one that has evolved to the apex of pathogenicity, the worst of the worst, but has lost some of its environmental fitness. All varieties in between likely exist.

 You've argued over the years that cholera epidemics are predictable. What's the basis for this argument?

I've watched tragedy after tragedy go by and there have been many of them and many of them have been predictable. History continues, new events occur, usually associated with some horrific natural disaster, and cholera shows up. Goma, Zaire, in 1994, with the largest number of documented cholera deaths in recent years, came about after a civil war and the establishment of refugee camps. At the time I was serving on the WHO steering committee for cholera vaccines and there was strong opposition, almost disbelief, to the idea that we could predict when and where cholera epidemics would occur. But my colleagues and I were strong advocates that refugee camps would be a place to target cholera prophylaxis. Vaccinate against the disease before it breaks out! Sadly, that was not considered seriously.

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