Tag Archives: disease

Representing Science to My Representative

My research is funded by the National Science Foundation, including the BEACON Center for the Study of Evolution in Action. BEACON is one of a dozen or so NSF Science and Technology Centers. Today, our Representative in the US Congress, Mike Bishop, came to BEACON for 40 minutes to discuss our center—what we do, what impacts our work has, and so forth.

It was something of a “fire hose” for Mr. Bishop, with several presenters trying to convey a lot of information very quickly.  However, he was engaged and asked thoughtful questions.  I think he left with an understanding of the importance of scientific and engineering research, including how fundamental curiosity-driven research can lead to applications.

I had 10 minutes to show him my lab and explain what we do and why.  When I make a short presentation like this one, I often write out a version in advance.  I don’t read it or memorize it by any means. However, writing it out helps get my thoughts in order—removing details that aren’t important, ordering ideas into a narrative, reminding me of what I most want to convey.

I’m sure I was not as clear or coherent as the text that follows.  I offer it here because it conveys the points I tried to make in the few minutes that I had as a representative of science speaking with a representative of the people.

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I want to show you one of the experiments in my lab.  We call it the long-term evolution experiment. It’s an unusual experiment because it’s been running for over 27 years.  And we keep it going because it’s been a scientific goldmine leading to new discoveries about how bacteria change over time.

It’s important that we understand bacteria and how they evolve for many reasons. Bacteria are best known because some of them can cause dangerous infections. But many of them protect us against infections—if our guts were not filled with harmless bacteria, then the dangerous ones would have a much easier time getting established in our bodies. Some bacteria also provide nitrogen to plants and perform other essential functions in the environment, including degrading some of the wastes that we produce.  And some bacteria are the workhorses of biotechnology.

To give one example of why bacterial evolution is so important:  If bacteria didn’t evolve, we would have defeated nearly all the pathogenic bacteria on Earth with antibiotics.  But they do evolve and become resistant to our drugs, and so the pharmaceutical industry has to spend billions of dollars trying to keep up with the evolving bacteria and viruses by developing new drugs to treat infections.

It’s possible to see evolution-in-action in bacteria, like we do here, for several reasons.

  • Their populations are huge.  The number of bacteria in just one of these little flasks is comparable to number of people in the United States.
  • They grow really fast.  Every day, there are about 7 generations of bacteria in each of the flasks.  So each day we see the great-great-great-great-great grandkids, so to speak, of the bacteria that were in our flasks yesterday. After 27 years, the experiment has run for over 63,000 generations.
  • And one more important thing about bacteria. We can freeze them and bring them back to life, and so we’ve got a frozen fossil record of the experiment.

When I started the experiment in 1988, there was no human genome project, and not even a single bacterial genome had been sequenced.  Now we go into our freezers and sequence the bacterial genomes to see how their DNA is changing over time.

The work we’ve done in this curiosity-driven experiment has inspired others who are using similar ideas and approaches to understand the rates and mechanisms of how bacteria evolve.

I’ll give two quick examples that show how our NSF-supported fundamental science gets translated into applications that are important for security and health.

First, you remember the anthrax letter attacks on Congress that occurred right after the 9/11 attacks. In the first few days after the anthrax attacks, I was contacted by the Defense Threat Reduction Agency for advice on how to identify the source of the strain used in that bioterrorism, and how to distinguish it from other related strains. And in the months that followed, I was asked for and provided advice to the FBI and other agencies investigating the attacks. Tracking the source of microbes in outbreaks—whether natural or terroristic in origin—requires understanding how they change over time.

Second, my colleague Prof. Martha Mulks studies bacteria that colonize the lungs of people with cystic fibrosis (CF).  There are about 30,000 people with this disease in the US alone.  It’s an inherited disease that makes people susceptible to lung infections and, unfortunately, those infections kill many kids and young adults with CF.  Some of the bacteria that infect the diseased lungs are not pathogens to most of us—they’re bacteria that live in soil and on plants, but when they get into the lungs of CF patients they evolve and adapt to that new environment. They also evolve resistance to the antibiotics that are meant to get rid of them. How exactly the various bacteria change to become better adapted to the CF lung environment is not known. Luckily, though, Martha Mulks and other foresighted scientists and clinicians have kept frozen samples of these bacteria over the years—just like we’ve done with the long-term experiment I described a moment ago. Now the BEACON Center is supporting work by a graduate student, Elizabeth Baird, who will analyze the DNA from old and new samples and apply some of the same approaches and methods that we’ve used and developed for the laboratory experiment to see how the bacteria have changed—how they have become resistant to antibiotics and otherwise adapted to the environment of the lungs of people who suffer from cystic fibrosis.

The bottom line is that the fundamental, curiosity-driven research that the National Science Foundation supports is also an engine for future applications—often ones that we may not even have dreamed of—as well as a training ground for the talented and dedicated young people who you can see working all around us in this lab and throughout the BEACON Center.

~~~~~~~~~~~

Rep. Mike Bishop (MI-08) and me in the lab.  [Photo: Danielle Whitaker, MSU.]

Rep Mike Bishop and me in lab, 14 Oct 2015

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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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Favorite Examples of Evolution

When the cold bites, When the review stings, When the news is sad, I simply remember these evolving things, And then I don’t feel so bad! — with apologies to Rodgers and Hammerstein

Over on Twitter, the biology students from George Jenkins High School in Lakeland, Florida, asked me and many others: “What’s your favorite example of evolution?”  There are so many fascinating examples that it’s hard for me to pick just one. So, here are half a dozen examples that are among my favorites.

  • The discovery by Neil Shubin and colleagues of Tiktaalik, an extinct fish (pictured below) from the Devonian that was poised to give rise to terrestrial vertebrates. You can read about this work in Shubin’s award-winning book, Your Inner Fish, which was also made into a PBS show.
  • The discovery by Svante Pääbo and colleagues of the Denisovans, an extinct lineage of humans, based on sequencing a complete genome from the finger bone of a girl who lived tens of thousands of years ago.
  • The analysis by Tami Lieberman, Roy Kishony, and colleagues of the genetic adaptation of an opportunistic species of bacteria to the lungs of patients with cystic fibrosis. I’ve blogged about that paper here.
  • Here’s one from the long-term experiment in my own lab — the evolution of the ability to use citrate that arose in just one of the 12 populations and after more than 30,000 generations. There are nice summaries of this work in Carl Zimmer’s blog here and here.
  • A study by Hod Lipson and Jordan Pollack on the evolution of robots. I remember hearing about this paper and being shocked: “Wait a second. Robots are expensive, and most things go extinct during evolution. How could they even afford do this?” I had to read the paper to realize they were evolving virtual robots in a physical simulation of the real world. They then built and tested the winners in the physical world. And indeed, the robots worked as they had evolved to do.
  • Applying the mechanisms of evolution to artificial systems is a fascinating approach useful for both biology and engineering. One of my favorite basic-science uses of this approach was a paper where we used digital organisms – computer programs that self-replicate, mutate, and compete for resources – to show how very complex functions could evolve if simpler functions were favored along the way. These simpler functions provided building blocks for the more complex functions, illustrating how evolution works by tinkering and borrowing already existing structures and functions and using them in new ways. Incidentally, this work involved collaboration between a computer scientist (Charles Ofria), a philosopher (Rob Pennock), a physicist (Chris Adami), and a biologist (me).

Readers: Please feel free to add your own favorite examples of evolution in the comments section below.

[The picture below shows the Tiktaalik fossil discovered by Neil Shubin and colleagues.  It was posted on Wikipedia by Eduard Solà, and it is shown here under the indicated Creative Commons license.] Tiktaalik

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Science Communication: Where Does the Problem Lie?

When concerns arise about the public’s understanding of science—say, on the efficacy of vaccines vs. their risks—I see many articles, tweets, etc., bemoaning poor scientific communication. Communication involves multiple parties and several steps. The science must be published, discussed widely, explained openly, and eventually stated in terms that non-specialists can understand. It also must be heard—and not merely heard, but fairly considered, carefully weighed, and then accepted, rejected, or put on hold by the intended receiver. That’s not all, of course. There are generally intermediaries—including teachers, reporters, doctors, business interests, politicians, religious leaders, and others—who must also convey the scientific information, but who may block, change, confuse, or distort the message either accidently or deliberately. And none of this is a one-way flow of information. There are multiple voices, and there are feedbacks as questions are asked, answered in new words or with new evidence, and so on. So it’s a complex problem, too complicated for a poll to shed much light. And of course, a poll here will get a highly non-random sample—mostly scientists, students, and others with an interest in science. But perhaps some professional pollster or organization interested in the communication of science can develop a proper poll along these lines (with information about a respondents’ professions, ages, affiliations, etc.), and with proposals about how to improve the situation at the various roadblocks. (Or maybe similar polls already exist. Please feel free to suggest useful references in the comments.) It might also be interesting to run the same poll except with prompts about different issues such as vaccinations, global change, and evolution. So here’s the poll: If you had to say, which one of the following groups shoulders the greatest blame, and thus has the greatest room for improvement, when it comes to the problems of communicating science?

  • Scientists
  • Professional intermediaries such as teachers, reporters, and doctors
  • Other intermediaries such as businesses, politicians, and religious leaders
  • The public

[The image below is from the British Council / BBC World Service site on teaching English. It is shown here under the doctrine of fair use.]

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Infectiously Fun Science

Science is sometimes frustrating. The work is often repetitive and even tedious. It can be hard to explain to our friends and families—and sometimes even to peers—what we’re doing and why we think it’s important and interesting. The current state of the academic job market is terrible.

But science is also often fun. There’s the joy of discovery, which grows out of the quieter excitement of seeing data come together to support or refute an existing idea and, perhaps, to generate a brand-new idea. If we’re lucky, we enjoy the recognition of our peers that comes when a paper is accepted, a grant funded, or a talk well received.

For those of us who study evolution, the frustrations can be magnified by critics and trolls who aren’t interested in evidence or reason, having already closed their minds to even the idea of evolution based on their narrow, literal reading—or, more often, someone else’s reading—of texts written in other languages long before science provided an evidence-based way to understand the world in which we live.

At the same time—and perhaps driven in part by the controversy surrounding evolution and religion—the field of evolution has long been blessed with great writers and speakers who are willing and able to engage the public. Twenty years before he published On the Origin of Species, Charles Darwin had already cemented his place in the public eye with his travelogue The Voyage of the Beagle. As a result, the Origin was an instant best seller on both sides of the Atlantic. And while Darwin shied away from speaking in public about his discoveries, Thomas Henry Huxley was a gifted orator who became “Darwin’s Bulldog” in public lectures and debates.

That tradition continues to this day. Some of my favorites include The Selfish Gene by Richard Dawkins, Wonderful Life by the late Stephen Jay Gould, Darwin’s Dangerous Idea by Daniel Dennett, and Your Inner Fish by Neil Shubin. Experts argue about scientific issues, minor and even major, contained in these books. But it’s hard for me to imagine an open-minded reader, someone interested in science and evolution, who would not find these books highly stimulating—even infectious in the sense of wanting to share them and the ideas they contain with others.

And speaking of infectious, new ways of communicating science have burst onto the scene since the printing press. For example …

Baba Brinkman is a rapper who raps about science, literature, public policy, and more. For your scientific enjoyment, here are three of my favorites from The Rap Guide to Evolution:

Performance, Feedback, Revision

Creationist Cousins

I’m A African

Here’s another from The Rap Guide to Human Nature:

Short Term Mating Dance

And here’s a brand-new one—on microbiology and disease—with a cameo appearance by yours truly and three students who work in my lab:

So Infectious

Whether you’re a scientist or not, I hope you’ll agree that these are worth sharing with your students, friends, and families!

[Image source: music.bababrinkman.com/album/the-rap-guide-to-evolution]

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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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