Published paper: Modeling antibiotic resistance gene emergence
Last week, a paper resulting from a collaboration with Stefanie Heß and Viktor Jonsson was published in Environmental Science & Technology. In the paper, we build a quantitative model for the emergence of antibiotic resistance genes in human pathogens and populate it using the few numbers that are available on different processes (bacterial uptake, horizontal gene transfer rates, rate of mobilization of chromosomal genes, etc.) in the literature (1).
In short, we find that in order for the environment to play an important role in the appearance of novel resistance genes in pathogens, there needs to be a substantial flow of bacteria from the environment to the human microbiome. We also find that most likely the majority of resistance genes in human pathogens have very small fitness costs associated with them, if any cost at all.
The model makes three important predictions:
- The majority of ARGs present in pathogens today should have very limited effects on fitness. The model caps the average fitness impact for ARGs currently present in human pathogens between −0.2 and +0.1% per generation. By determining the fitness effects of carrying individual ARGs in their current hosts, this prediction could be experimentally tested.
- The most likely location of ARGs 70 years ago would have been in human-associated bacteria. By tracking ARGs currently present in human pathogens across bacterial genomes, it may be possible to trace the evolutionary history of these genes and thereby identify their likely hosts at the beginning of the antibiotic era, similar to what was done by Stefan Ebmeyer and his colleagues (2). What they found sort-of corroborate the findings of our model and lend support to the idea that most ARGs may not originate in the environment. However, this analysis is complicated by the biased sampling of fully sequenced bacterial genomes, most of which originate from human specimens. That said, the rapid increase in sequencing capacity may make full-scale analysis of ARG origins using genomic data possible in the near future, which would enable testing of this prediction of the model.
- If the origins of ARGs currently circulating in pathogens can be established, the range of reasonable dispersal ability levels from the environment to pathogens narrows dramatically. Similarly, if the rates of mobilization and horizontal transfer of resistance genes could be better determined by experiments, the model would predict the likely origins more precisely. Just establishing a ball-park range for the mobilization rate would dramatically restrict the possible outcomes of the model. Thus, a more precise determination of any of these parameters would enable several more specific predictions by the model.
This paper has a quite interesting backstory, beginning with me having leftover time on a bus ride in Madison (WI), thinking about whether you could quantize the conceptual framework for resistance gene emergence we described in our 2018 review paper in FEMS Reviews Microbiology (3). This spurred the first attempt at such a model, which then led to Stefanie Heß and me applying for support from the Centre for Antibiotic Resistance Research at the University of Gothenburg (CARe) to develop this idea further. We got this support and Stefanie spent a few days with me in Gothenburg developing this idea into a model we could implement in R.
However, at that point we realized we needed more modeling expertise and brought in Viktor Jonsson to make sure the model was robust. From there, it took us about 1.5 years to refine and rerun the model about a million times… By the early spring this year, we had a reasonable model that we could write a manuscript around, and this is what now is published. It’s been an interesting and very nice ride together with Stefanie and Viktor!
- Bengtsson-Palme J, Jonsson V, Heß S: What is the role of the environment in the emergence of novel antibiotic resistance genes? A modelling approach. Environmental Science & Technology, Article ASAP (2021). doi: 10.1021/acs.est.1c02977 [Paper link]
- Ebmeyer S, Kristiansson E, Larsson DGJ: A framework for identifying the recent origins of mobile antibiotic resistance genes. Communications Biology 4 (2021). doi: 10.1038/s42003-020-01545-5
- Bengtsson-Palme J, Kristiansson E, Larsson DGJ: Environmental factors influencing the development and spread of antibiotic resistance. FEMS Microbiology Reviews, 42, 1, 68–80 (2018). doi: 10.1093/femsre/fux053 [Paper link]
The Wisconsin Blog is on again
I’ve been having a very intense start of the year with the move to the US and getting the family accustomed to Madison (which has taken time and energy, but gone really well). I just wanted to make you aware of that I have started posting at the Wisconsin Blog again and hope to be sharing research related stuff from my year in the US there. For more personal stuff, our family has set up a blog (in Swedish) at this address: https://palmeiamerikat.blogspot.com. You are very welcome to follow our adventure there!
And the experiments have started!
It’s been a long time before I have written something here, mostly because making ourselves at home in Madison have take some time; then we go the flue; and then there have been a lot at work after that. But now i will try to have another go at writing somethings on the Wisconsin Blog. First, a look at my (already messy) desk here at the Wisconsin Institute for Discovery.
And then, a look at my lab space, which I have a view of straight from my desk, through a glass window.
This week, I have started experiments with exposing our little model community to antibiotics and it looks like I’m getting potentially exciting results. I have to sit down with the data today to see if there’s statistical differences, but from the looks of the biofilms, there is potential here.
Next week I will try to start experiment with sand columns and see if I can replicate some of this in this setting as well. It is interesting being back in the lab, and I feel that this an experience that will be very valuable for me going forward. I look forward to the days later this spring when I will start generating sequence data from my own experiments!
So this morning, I packed my stuff, cleaned out my room and went to WID for the last time this year. I had time to say goodbye to everyone in the lab but Bailey, and I have to admit that I feel a little bit sad leaving. This is a really good place, filled with very good people, in a very beautiful town. I will miss you Handelsman lab, and I will miss you Madison. On the other hand, tomorrow I will be picking up my daughter after preschool for the first time in a month.
I am now waiting for my flight at the airport. I prepare for a long night of lost sleep (as I cannot sleep on airplanes). I am endlessly happy that I will be able to combine these two fantastic worlds next year when we are moving here altogether. Until then, farewell Madison – see you soon again.
I guess this concludes the blog for this time around. Please check back this winter when we’re going here the next time. This is Johan in Madison – over and out.
Something to live up to
Around the biochemistry building of the University of Wisconsin-Madison campus (and perhaps also elsewhere), there are a lot of these signs, highlighting discoveries that were made in Madison. And they really have a history to be proud of. This place is where both bacterial conjugation and transduction was discovered, paving the way for much of the genome editing and studies we take for granted today. And they also did the basics required to generate knock-out mice for genetics studies. I could go on, but I I think I made my point. This place has a lost of history. And I doubt that my slightly messy project will live up to these groundbreaking discoveries.
This Monday is Labor day in the US. Which means, I work. After having Wednesday off from lab work, me and Manuel finished up my final experiments for this round yesterday evening, so I have spent this afternoon doing some data analysis. Or rather, I should have spent the day doing data analysis, but it was boring, so instead I have mostly been scripting this… Hopefully that will pay off at a later date when I analyze more plates…
Before that, I went to see a house, which I liked a lot, so hopefully I will be able to sign a contract for this before I leave for Sweden again on Wednesday. Fingers crossed, over and out!
Today, I went to the big Saturday thing in Madison – the Farmers Market. Apparently this is one of the largest (if not the largest) farmers markets in America, and it’s huge. Farmers (and sellers of some other stuff like yarn) gather all around the State Capitol, and when I arrived at around half past eleven, there were so many people there that you had to just enter into the crowd and follow it in the given walking direction. The sign “Stay right for hot & spicy cheese bread” was right on it; you had to stay in the right lane to get there. But there was so much nice stuff. And then on the opposite side of the stands, there were families picnicking on the lawn and kids running around. I imagine that this will be a nice Saturday outing next Spring when we bring the kids here. For now, I ended up with three apples and some sprouts. I need to finish the food in the fridge before I go back home on Wednesday. Is it time to go home already? It’s been an eternity, but time has also passed so fast…
The rest of the day I spent walking around by the Lake Monona and Lake Wingra, taking a break for a coffee at Colectivo Coffee. Very nice place with excellent pourovers. But now my feet hurts and I need to get some sleep!
Students are coming back
I’ve spend the lion’s share of the past few days in the lab, working quite late to obtain supercool results that we will now verify over the weekend. It’s very exciting to be able to generate useful data already during your first week in the lab (after not doing wet lab work for years), but mostly this is thanks to Manuel. Anyway, look at the beauty of those plates! My new favorite color must be crystal violet.
Another thing that has happened over the past week is that the students are beginning to come back her for the autumn semester. This means nice little paintings on the ground, lots of things happening downtown, but also that it’s harder to sleep since the previously quiet area of college dorms is not seeing quite a significant amount of nightlife. Large packs of students passing by my window at night, talking loudly. It’s mostly nice though. There are many parallels between Uppsala and Madison – both are cities heavily centered around their universities, and both seem to die a little during summers when the students move out. The differences mainly are that Madison is much more beautifully located between three lakes, that Uppsala has a much older history, and that Madison seems to have quite a bit of nightlife also in the summertime.
On Monday I will go to see a house to rent next year. Please keep your fingers crossed that it’s good and, if so, that we’ll get it! Otherwise housing has been a bit of a hassle, since everyone wants to rent now before the autumn semester. But I hope that that problem will no longer be a problem on Monday. Have a nice weekend!
Manuel, my hero
Okay, first of all this is a shoutout post to Manuel Garavito, who has been putting up with me for the last two days – my first two days in a wet lab for several years. Manuel has been beyond fantastic in showing me their basic protocols and having patience with my rusty lab skills. If this project will work out, it will very much be because of him.
This weekend, there haven’t been a lot of time for other things than lab work, but I spent Friday evening at the Memorial Union where I happened to stumble into a concert with Brazilian (I think, not sure) music. And on Saturday evening I went out to the Hop Cat, where I tasted the fantastic beer Psychedellic Cat Grass and got taught the basics of American football by a woman who was also there on her own, apparently to watch the game. So, I’m doing my well but working my ass off with things I am not really that good at. Yet.
Back in Madison
Hey, sorry for disappearing for more than a week. The EDAR conference (more on that in a later post) was super-intense and the weekend with my Gothenburg research group in Munising in northern Michigan was fantastic but didn’t really leave any time for writing. And after that I have been quite messed up emotionally, feeling very lonely and started doubting my project and … well everything. But it’s looking better now again. Yesterday evening I was out dancing lindy hop at The Brink. Although I only did a few dances, it was very nice to do something that was all about feeling good and playing, and not so serious.
Today I have instead spent my evening doing grocery shopping at Whole Foods (what a fantastic store that is!) and checking out the areas where the University of Wisconsin keep their university housing. Oh, how I wish that we could get somewhere to live there. The surroundings are absolutely beautiful and there were kids everywhere on the lawns. That said, the queues for staying there are most likely very long. By the way, if anyone would have an insider tip on where and how to find good places to live in Madison, all input is appreciated. Tonight, Madison has been good to me.