Why are not all E. coli resistant to antibiotics?

Last summer gave a talk at a Gordon Conference about transmission and evolution of drug resistance in HIV and E. coli. When I was done with my talk, there was time for questions. Dmitri Petrov asked what I thought about why resistant and susceptible strains of bacteria co-exist. I had to admit that I hadn’t really thought about that.

This question of co-existence (why aren’t all bacteria resistant or all of them susceptible?) it not a new one. In fact, about a week after the Gordon Conference, I talked to Marc Lipsitch who has worked on this question for many years. It was just not on my radar. Until last summer.

The question of co-existence marinated in my head for over the summer. I read papers about it. Looked at the data I was analyzing. And then sometime in the fall it suddenly hit me! I saw a solution to the question that was real easy. This is what I think may be happening: Resistance evolves when a bacterial strain finds itself in a person who is treated with antibiotics. But because most of us aren’t on antibiotic treatment most of the time, these resistant strains tend to have lower R0 values than susceptible strains (that is, the resistant strains don’t spread as effectively). Therefore in the human population at large, existing resistant strains are losing against the susceptible strains.

I had been studying the many origins of resistance (resistance in E. coli and other bacteria evolves very often – lots of convergent evolution), and I had been studying the cost of resistance (I think most resistant E. coli strains tend to die out – thought this is not easy to prove). These two ingredients together can explain the co-existence of resistant and susceptible strains.

Early October I emailed Dmitri: “Dmitri, I think I have the answer to your question!”. Dmitri answered: “Exciting! But you forgot to attach the manuscript”. Me: “Oh, I didn’t write it up yet! It is just in my head.”

So I started writing because that’s how academic science works!

The manuscript now lives on Medrxiv. I have submitted it to Nature (desk-rejected) and to Science (reviewed and rejected). Traditionally, after a rejection from a high-profile journal, one would send a manuscript to another journal right away, but one of the reviewers from Science suggested using a particular Norwegian dataset, instead of the Enterobase data I had used for the manuscript. I really liked that idea (as well as some other ideas from the reviewers). So I decided to pause and do more analysis. Some of the new data made their way into my talk for the TAGC conference in Washington DC last week.

If you are curious to hear where I am at with this project, here is the video of my talk:

Collaborative science in the 1850s

I just finished reading a nice book about John Snow and London in the mid-19th century. The book tells the story of Snow’s idea that Cholera is transmitted through water (and not air). The book has a website here.

The book is from 2006, so chances are that you have already read it.

I was reading the book in the hope to learn more about diseases and epidemiology, but I think I ended up learning more about research in general. I also learned that London was a smelly place in the 1850s.
The book is full of wonderful lessons for a young researcher. For example, the book shows that

1. Research is hardly ever done by one person alone. John Snow was probably a great researcher, but he couldn’t have done his important work on Cholera without the help of statistician Farr and reverend Whitehead. Even in the 1850s, science was a collaborative enterprise.
2. It is OK if people don’t believe you. In fact, a lot of the evidence for the waterborne transmission route of Cholera came from Whitehead, who was on a mission to disprove Snow’s theory.
3. Changing opinions takes time. It took many years, lots of data and papers before people started to believe Snow’s idea, even though Snow was well known and a respected physician.

The map that figures in the title of the book didn’t reproduce well on my Kindle, so I had to look it up on Wikipedia later.

John Snow Cholera Map

Honestly, I find the map not very impressive. Sure, it may be important in the history of epidemiology and the history of data visualization, but I was slightly disappointed that the map wasn’t clearer. It is supposed to show that all the deaths occurred near one pump. But The locations of the pumps are not very clear at all. It also doesn’t show the surprising pockets of Cholera absence that are described in the book and that were important for Snow’s inference.

The book is highly recommended!