Tag Archives: Darwinian medicine

A Day in the Life of …

Today was a great day – busy and wonderful. Pretty typical, I’m happy to say, though a bit busier than usual but all of it great.

Woke up to beautiful Spring day in East Lansing and walked 1.7 miles to work at MSU.

Did the usual email stuff.

Worked on getting ready for teaching for a class on evolutionary medicine taught by my colleague Jim Smith. Today’s focus will be the paper by Tami Lieberman et al. on the evolution of Burkholderia dolosa in cystic fibrosis patients during an outbreak in Boston. Last night I re-read the paper for the umpteenth time, and I still enjoyed it. Today I organized a series of questions for the students – a very interactive and smart group – around three parts.

Part I: Some background about CF, the inheritance of this disease, the frequency of the disease, how that frequency allows one to estimate the frequency of carriers, why the allele might be so common (not understood), side questions about sickle-cell anemia and why it’s so prevalent, and why, if it’s inherited, the paper we read is all about infections.

Part II: Preparing slides so we could work our way, figure by figure and panel by panel, through all of the main points in Lieberman et al.  (Reminder: Explain to students how scientific papers are often written around figures.  Once the figures and tables are there, then start on the results, etc.)

Part III: Follow up questions about the paper, the system, the interface of epidemiology and evolutionary biology, prospects for the future of this field and the students’ careers (most in this class are premed, many with a research bent), etc. And whatever questions they might want to ask of me.

Sometime in the middle of doing all that: Chatted with second-year grad student Jay Bundy, who is reading some of Mike Travisano’s terrific earlier papers on the LTEE. Specifically, why do we sometimes express fitness as a ratio of growth rates (measured in head-to-head competitions) and sometimes as a difference in growth rates?

Also in the middle of doing all that: Had phone conversation with former Ph.D. student Bob Woods, now also an M.D. specializing in infectious disease, about a faculty job offer he has (congrats, Bob!), some of the issues he needs to clarify or negotiate, and some of the amazing work he’s now doing on the population dynamics and evolution of nasty infections.

Email from grad student Mike Wiser that our paper, submitted to PLOS ONE, has been officially accepted. We had posted a pre-submission version at bioRxiv – now it’s gone through peer-review and revisions and is accepted for publication. Congrats, Mike!

Got a draft of the fourth and final chapter of Caroline Turner’s dissertation. The first three chapters are in great shape. Congrats, Caroline! With teaching looming, I had only time to review the figures, tables, and legends on this one, and made some small suggestions. On to the text tomorrow … It’s a beautiful body of work on two fascinating aspects of the interplay between ecology and evolution that have emerged in the LTEE and another evolution experiment that Caroline performed. Stay tuned for these papers!

Took a phone call from an MSU colleague who has friend with a child in high school who is interested in microbiology, who is visiting MSU, and who wanted to see the lab. Yikes, I gotta run teach! But postdoc Zack Blount kindly agreed to give a guided tour as I headed off to teach.  Thanks, Zack!

Beautiful day continues as I walk to teach in another building. Touch base with Jim Smith about what I plan to cover.

Two straight hours of teaching (one 5-minute break) in an overly hot room. Almost all of it interactive, with me asking questions and the students conferring in small groups and then responding. Very interactive, very bright students! The two hours were nearly up, with little time for my third, post-paper set of questions. But all of the students stayed (despite the beautiful weather, hot room, and the dinner hour at hand) an extra 15-20 minutes for a couple of my questions and some great ones from them about the LTEE and the future prospects for microbial evolution in relation to medicine.

It’s 6:20 pm: I’m mentally exhausted but equally invigorated. Beautiful Spring day continues as I walk home. I’m greeted by our lovely hound, Cleopatra. Exercise and feed her. Then an even more lovely creature, Madeleine, returns home and I greet her.

Check email before dinner. Find that paper with grad student Rohan Maddamsetti and former postdoc Jeff Barrick has been provisionally accepted, pending minor revisions, at Genetics. We posted a pre-submission version of that paper, too, at bioRxiv. Though we still need to do some revisions, I think it’s fair to offer congrats to Rohan and Jeff, too!

Time to crack open a bottle of wine and have some dinner. Fortunately, some of the pre-packaged dinners are pretty tasty and healthy, too, these days ;>)

Refill wine glass. Sit down and start to write a blog on a day in the life of …

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Google Scholar, a Forthcoming Book, and Doonesbury

I just looked at my Google Scholar page this afternoon.  I find it useful to see who has been citing our research.  (And, I admit, it is kind of fun to see those h-indices tick up.  I will also admit that I liked baseball statistics when I was a kid.  Just yesterday, I was  recounting to friends the bold move by the Detroit Tigers in the 1968 World Series to play one of their good-hitting outfielders at shortstop to get an extra bat into the lineup.)

So today, Google Scholar listed several new co-authors that I should add to my roster … and impressive ones at that.  How’s that?

Google Scholar picked up on a forthcoming edited volume, The Princeton Guide to Evolution, which will be coming out soon.  Jonathan B. Losos is the editor-in-chief, with eight more of us also serving as editors:  David A. Baum, Douglas J. Futuyma, Hopi E. Hoekstra, Richard E. Lenski, Allen J. Moore, Catherine L. Peichel, Dolph Schluter, and Michael C. Whitlock.

Easy work?  Hardly!  I edited the final section on “Evolution and Modern Society.”  That may sound a bit fluffy, but I was, and am, really excited by it.  In this section alone, there are 15 articles organized around four themes: (i) evolution and disease, (ii) evolution and technology, (iii) evolution and what it means to be human, and (iv) evolution in the public sphere.

I lined up great people to write on interesting and important topics —

  • Paul Turner on “Evolutionary Medicine”
  • Dieter Ebert on “Evolution of Parasite Virulence”
  • Dan Andersson on “Evolution of Antibiotic Resistance”
  • Paul Keim and Talima Pearson on “Evolution and Microbial Forensics” (including how evolution was used to investigate the anthrax postal attacks right after 9/11)
  • Amy Cavanaugh and Cameron Currie on “Domestication and the Evolution of Agriculture” (including how ants discovered farming long before we humans did)
  • Brad Shaffer on “Evolution and Conservation”
  • Erik Quandt and Andy Ellington on “Directed Evolution”
  • Rob Pennock on “Evolution and Computing” (including how evolution was used to design antennae that have been launched into space)
  • Mark Pagel on “Linguistics and the Evolution of Human Language”
  • Elizabeth Hannon and Tim Lewens on “Cultural Evolution”
  • Alan Templeton on “Evolution and Notions of Human Race”
  • Alan Templeton, again, on “The Future of Human Evolution” (no, humans have not stopped evolving)
  • Francisco Ayala on “Evolution and Religion”
  • Genie Scott on “Creationism and Intelligent Design” (including how the different flavors of creationism have evolved over time)
  • And, last but not least, Carl Zimmer on “Evolution and the Media” (including blogs, of course)

Oh, and I wrote an Introduction to the section that pulls the four themes together and explains how they all intersected in one epic Doonesbury comic strip.  But you’ll have to buy, or borrow, the book to see how I pulled everything together.  (No, I don’t get any royalties, but I got a small honorarium.)

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Lieberman et al., 2011, Nature Genetics

My second “must-read” paper is a recent one.  Unlike the last paper I discussed, I suspect that most of you have not read this one and probably don’t even know about it.  I hope this post will convince you to go out and read it.

And if you do, you might also use this paper in your teaching.  It should be a terrific paper to explain or discuss in all sorts of courses from an undergrad evolution course filled with pre-meds to a graduate-level seminar on … well, almost anything, from genomics and molecular evolution to Darwinian medicine and evolution in action.

Lieberman TD, Michel JB, Aingaran M, Potter-Bynoe G, Roux D, Davis MR, Skurnik D, Leiby N, LiPuma JJ, Goldberg JB, McAdam AJ, Priebe GP, Kishony R.  2011.  Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes.  Nature Genetics 43, 1275-1280.

There was also an accompanying News and Views piece by yours truly.

Lenski RE.  2011.  Chance and necessity in the evolution of a bacterial pathogen.  Nature Genetics 43, 1174-1176.

Short summary:  This paper provides a striking demonstration of the power of combining genomic, epidemiological, and evolutionary data and analyses.  Tami Lieberman and Jean-Baptiste Michel, two graduate students in Roy Kishony’s group, and colleagues sequenced 112 clonal isolates of an opportunistic pathogen, Burkholderia dolosa, that were sampled from 14 patients over the course of 16 years.  Using phylogenomics, they first traced the history of transmission events and used the resulting phylogeny to distinguish between mutations that were shared by descent and those that arose within a particular patient.  They then identified 17 genes that exhibited significant signatures of parallel evolution, and they inferred that mutations in those genes contributed to the pathogen’s adaptation to the host environment.

Some additional context and findings:  The patients in this study were individuals with cystic fibrosis (CF), an inherited disease that makes them vulnerable to chronic and life-threatening infections of the lungs.  A number of different bacterial strains can cause these opportunistic infections, and they are sometimes transmitted between CF patients in the same clinic or other settings.  In the 1990s, there was an outbreak of B. dolosa infections among 39 CF patients in Boston.  Foresighted clinicians and researchers saved isolates from these patients, and some of the isolates were then sequenced and analyzed in this study.

The genes that Lieberman et al. identified as having mutations under positive selection in the CF host environment include several likely candidates, specifically genes related to therapeutic interventions (antibiotic resistance) and host immune responses (cell-surface antigens).  However, the genes with mutations under positive selection also included others not previously known to play a role in these infections, including some involved in oxygen-dependent regulation and others of unknown function.

The evidence for positive selection based on parallel evolution was further supported in two additional ways.  For two phenotypes (antibiotic resistance and antigenicity) that can be readily scored in the lab, genome-wide association tests provided compelling evidence of a causal connection between specific mutations and phenotypic differences among isolates.  More generally, the dN/dS ratio – reflecting the relative rates of change at non-synonymous and synonymous sites in protein-coding sequences – was substantially elevated (above unity) in the 17 genes identified on the basis of parallel changes, but that ratio was not elevated in the remainder of the genome.

Why I like this paper so much:  First, this paper shows just how important evolutionary thinking is becoming to fields like genomics and medicine.  Remember how dreary those early genome papers became after the novelty of seeing foldout figures with giant circles (or lines, for those of you working on eukaryotes), funny colors, and tiny labels had worn off?  Sure, there was phylogenetic information to be gleaned, and maybe some hints about something interesting that happened in one lineage or another.  But if history is “just one damned thing after another”, then genomics was looking like “just one damned nucleotide after another.”  The paper by Lieberman et al., by contrast, shows the beauty and power of evolutionary thinking when applied to an interesting collection of genomes.  This study shows how a rigorous evolutionary analysis can generate new insights and new leads with respect to mechanisms of pathogenesis and potential targets of therapy.

Second, this paper provides a wonderful illustration of just how far science and technology have come.  It was four decades from Watson and Crick’s elucidation of the structure of DNA in 1953 to the publication of the first bacterial genome sequence in 1995, undoubtedly at great expense.  Now, even a basic-science, curiosity-driven lab like mine can afford to sequence dozens of bacterial genomes to study the dynamics of evolution and the complex genetic basis of a novel phenotype.  And when it comes to health-related and other applied research, advances are no longer limited by the costs of obtaining complete genome sequences of many samples, but rather by the ingenuity of scientists in analyzing, interpreting, and understanding the data.  The huge advances in computing power in recent decades were also essential for this study; for example, the authors generated the null distribution for genetic parallelism by randomizing, 1000 times over, the placement of the 561 independent mutations seen in their data across the ~6.4 million sites in the B. dolosa genome.

Third, I am fascinated by the tension between “chance and necessity” – randomness and repeatability – in evolution.  Understanding the cause of that tension was the point of Luria and Delbruck’s paper; exploring the effects of that tension lies at the heart of our long-term evolution experiment; and exploiting that tension provides the power behind the inferences in the study by Lieberman et al.

Fourth, the senior (last) author on the paper, Roy Kishony, visited my lab for a few days to discuss evolution when he was a graduate student making the transition from physics to biology.  Roy has gone on to do beautiful work, both basic and applied, in the area of microbial evolution.

Last, but not least, I use Lieberman et al. as a discussion paper in a course that I co-teach on “Integrative Microbial Biology.”  Most of the students are in their first semester of graduate school, and they are interested in different areas of microbiology – from infectious disease and immunology through genetics and molecular biology to ecology and evolution.  This paper interests all of them and, more importantly, it helps them to see how these different fields of inquiry can and do fit together.

Lieberman Fig 2b

The figure above comes from Lieberman et al., 2011, Nature Genetics; it is shown here under the doctrine of fair use. The figure illustrates the transmission history inferred from the authors’ phylogenomic analysis of B. dolosa isolates from 14 infected patients.

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