Tag Archives: microbiology

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.

~~~~~~~~~~~

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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63,000 Strong

Ever wonder about those big numbers posted in a window in that tall building on the east side of Farm Lane, across from the entrance to the MSU Dairy Store?

Right now, the digits read 63000. That’s the number of generations in an experiment that’s been running in my lab for over a quarter century.

We call it the LTEE, which stands for the Long-Term Evolution Experiment. There are 12 populations of E. coli bacteria in the experiment, and they all started from the same strain.

Every day—weekends and holidays included—a member of my team takes 1% of the cells in each population and puts them in a flask with fresh food. Over the next 24 hours, the population grows 100-fold and then runs out of food. These dilutions and renewals go on day after day, week after week, month after month, year after year, decade after decade. I hope the experiment will continue long after I’m gone, so that someday someone can write “and century after century.”

Bacteria grow by binary fission: 1 cell makes 2 cells, 2 cells make 4, 4 make 8, etc. So the 100-fold growth in the fresh medium represents about 6.6 doublings, or generations, every day. (There’ve been some interruptions since the LTEE began in 1988, but not many.)

Now consider a bacterial cell that gets a mutation in its DNA that lets it acquire more food and grow a little faster. That cell will leave more descendants than its competitors—that’s adaptation by natural selection. Over time, the bacteria are becoming stronger and fitter in their flask-worlds.

By watching the 12 populations evolve, we can answer questions about the dynamics and repeatability of evolution in a group of organisms—bacteria—that are essential for life on Earth as well as important players in health and disease. We measure the growth rates of the bacteria, we sequence their DNA, and we see just how much evolution can achieve even in short order.

Oh, about the sign. Zachary Blount is a talented postdoc who works on this project, and he likes to have fun with science. He put up the window display which, if you look closely, has a picture of Charles Darwin on the left, “The E. coli Long-Term Evolution Experiment” over the number, and “Generations and Counting” to the right. Every 1,000 generations or so, Zack updates the sign.

63K window

[Photo credit: Zachary D. Blount]

Note:   This piece first appeared at eastlansing.org after an invitation from Alice Dreger to explain the numbers in the window to our community.

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Tiny Things that Live in Little Bottles

As I mentioned in my previous post, it can be a fun challenge to explain your scientific research to people who aren’t scientists.

A week or so ago I came across a website that challenges you to explain something complicated using only the thousand most commonly used words.

So here’s my effort about our long-term evolution experiment with E. coli:

My team works with really tiny things that live in little bottles. We watch the tiny things change over time – over a really long time. The tiny things that do the best have learned to eat their food faster and faster, before the other guys can eat their lunch, so to say.  Well, the tiny things don’t really learn, but it’s kind of like learning – and even better, the best ones pass along what they learned to their kids.  A really cool guy came up with the idea of how this works more than a hundred years ago. My team’s work shows he got it pretty much right. But there’s a lot of stuff he didn’t know, and we’re figuring that out, too.

Several other biologists followed up including Nicole King, Graham Coop, and Josie Chandler (the links are to the simple-words-only descriptions of their own research).

Give it a try, and add your contributions in the comments below!

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Thirty Years

No, the LTEE did not suddenly jump forward by almost 3 years. That milestone will be reached on February 24, 2018.

Next Friday is the end of the semester at MSU and, for me, it will mark 30 years that I’ve been on the faculty: six at UC-Irvine, and 24 here at MSU. (I also taught for one semester at Dartmouth as a sabbatical replacement, while I was doing a postdoc at UMass.)

Holy cow: 30 years. Where did all that time go?

Well, a lot of it was spent advising, supervising, and mentoring graduate students. And those have been some of the most interesting, enjoyable, and rewarding professional experiences that I can imagine.

In fact, this afternoon Caroline Turner defended her dissertation – congratulations Dr. Turner! Her dissertation is titled “Experimental evolution and ecological consequences: new niches and changing stoichiometry.” It contains four fascinating and meaty chapters, two on the interplay between evolutionary and ecological processes in the LTEE population that evolved the ability to grow on citrate, and two on evolved changes in the elemental stoichiometry of bacterial cells over experimental time scales.

Caroline is the 20th student to complete her Ph.D. with me serving as the advisor or co-advisor. Here they all are, with links to their professional pages or related sites.

  1. Felisa Smith, Ph.D. in 1991 from UC-Irvine.
  2. John Mittler, Ph.D. in 1992 from UC-Irvine.
  3. Mike Travisano, Ph.D. in 1993 from MSU.
  4. Paul Turner, Ph.D. in 1995 from MSU.
  5. Greg Velicer, Ph.D. in 1997 from MSU.
  6. Brendan Bohannan, Ph.D. in 1997 from MSU.
  7. Phil Gerrish, Ph.D. in 1998 from MSU.
  8. Farida Vasi, Ph.D. in 2000 from MSU.
  9. Vaughn Cooper, Ph.D. in 2000 from MSU.
  10. Danny Rozen, Ph.D. in 2000 from MSU.
  11. Kristina Hillesland, Ph.D. in 2004 from MSU.
  12. Elizabeth Ostrowski, Ph.D. in 2005 from MSU.
  13. Bob Woods, Ph.D. in 2005 from MSU.
  14. Dule Misevic, Ph.D. in 2006 from MSU.
  15. Gabe Yedid, Ph.D. in 2007 from MSU.
  16. Sean Sleight, Ph.D. in 2007 from MSU.
  17. Zack Blount, Ph.D. in 2011 from MSU.
  18. Justin Meyer, Ph.D. in 2012 from MSU.
  19. Luis Zaman, Ph.D. in 2014 from MSU. (Charles Ofria was the primary advisor.)
  20. Caroline Turner, Ph.D. in 2015 from MSU.

There are also 8 doctoral students at various stages currently in my group at MSU including Brian Wade (Ph.D. candidate), Mike Wiser (Ph.D. candidate), Rohan Maddamsetti (Ph.D. candidate), Alita Burmeister (Ph.D. candidate), Elizabeth Baird, Jay Bundy, Nkrumah Grant, and Kyle Card.

My own advisor – the late, great Nelson Hairston, Sr. – said that he expected his graduate students to shed sweat and maybe even occasional tears, but not blood. I would imagine the same has been true for my students.

Thirty years, holy cow. Time flies when you’re working hard and having fun!

Added November 4, 2015:  And now #21 in my 31st year, as  Mike Wiser successfully defended his dissertation today!

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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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Funding the LTEE—past, present, and future: Questions from Jeremy Fox about the LTEE, part 4

EDIT (23 June 2015): PLOS Biology has published a condensed version of this blog-conversation.

This is the 4th installment in my responses to Jeremy Fox’s questions about the long-term evolution experiment (LTEE) with E. coli. This response addresses his 5th and 6th questions, which are copied below.

 ~~~~~

  • How have you maintained funding for the LTEE over the years, and how hard has it been? The difficulty of sustaining funding for long term work is a common complaint in ecology, and I’m guessing in evolution as well. And of course, if people think that they won’t be able to sustain funding for a long-term project, they’re less likely to start one in the first place. At best, they’ll try to do it by piggybacking short-term studies (or short-term rationales) on the long-term work, so that the long-term work can be sustained via a series of short-term grants. When you first proposed the LTEE to NSF or whoever, presumably you didn’t say “I propose to set up 12 replicate lines of bacteria, keep them going for decades, and see what happens”. And when you went back for your first (or second, or third…) renewal, presumably you still didn’t say “a bunch of cool stuff has happened already, so please give me more money to keep it going, just to see if anything else cool happens.”
  • Related to the previous question: Has it become easier to get funding to keep it going as you’ve gone along? Has it gotten to the point where the experiment (and you?) is widely seen as an “institution”? So that rather than needing to justify it anew every few years, people are basically eager to hand you money to keep it going, no questions asked?

 ~~~~~

Past.  All in all, I’ve been very fortunate with funding for my research. My first attempt to get the LTEE funded was rejected, but around that time I received a Presidential Young Investigator Award from the National Science Foundation (NSF) that gave me considerable freedom to pursue the research directions that most interested me. Various grants have supported the LTEE since then including, for the past 10 years, an NSF LTREB grant (LTREB stands for long-term research in environmental biology).  LTREB grants are very small, but mine provides core support to keep the lines going.  Other funds are required to do anything more than some basic quality control and assays. My professorship at MSU—named after John Hannah, who was president of MSU for 28 years, about the duration of the LTEE!—has provided discretionary funds that have been invaluable, allowing us to explore new scientific directions and techniques as they become interesting and available, without requiring us to first secure funding. And the graduate students and postdocs in my group have been very talented, and they’ve often been awarded fellowships that fund the essential brain-power and hard work that has made the LTEE so successful.

Present.  I take proposal writing very seriously, always emphasizing both the overarching questions that have been with the LTEE since it began and the specific aims that arise from new discoveries and technical advances. One always has to make the case for why a particular project, individual, or team merits support. So I wouldn’t say it has gotten easier to get funding, especially given the decline in funding rates. But I do sense that reviewers have, on balance, become increasingly excited by the LTEE project over the years, as it has borne a lot of fruit. In fact, the NSF program officer has told me that the LTREB grant will be funded again for the next 5 years. During the pre-proposal phase (yes, a pre-proposal was required for a project that has run for over a quarter century!), the panel summary called the LTEE “this community’s Hubble Telescope.” Now that was certainly gratifying!

Future.  The big challenge going forward will be to secure funds that will allow the LTEE to continue after I’m gone. Many colleagues have told me that the LTEE must continue, and I agree. (I’m not planning on retiring anytime soon, but I think it’s wise to hand off a project sooner rather than wait to the last hour.) I like to call the LTEE the experiment that keeps on giving, so the challenge is to find a way to make that happen.

I realize that not every scientist will have the same good fortune that I’ve had. Indeed, by continuing “someone else’s experiment” a young scientist might even be viewed by some as unoriginal and thus unworthy of the privileges of tenure and funding. To overcome that stigma, I’d like to secure funds to ensure that, not only can the LTEE continue, but that its continuation is rewarding rather than burdensome to future scientists. After all, it comes with its own inherent challenges—including the fact that the populations are tended every day as well as management of the ever-growing collection of frozen samples.

My thinking is that each successive scientist responsible for the LTEE would, ideally, be young enough that he or she could direct the project for 25 years or so, but senior enough to have been promoted and tenured based on his or her independent achievements in a relevant field (evolutionary biology, genomics, microbiology, etc.). Thus, the LTEE would likely continue in parallel with that person’s other research, rather than requiring his or her full effort, just like my team has conducted other research in addition to the LTEE. The goal, then, is to provide the future project leaders with the benefits of continuing the LTEE while relieving them of the most onerous burdens.

So as I’ve said before, “If you know anyone who would like to endow a million-year experiment, have them get in touch with me.”

[This picture shows the Hubble Space Telescope. It was taken on a servicing mission in 1997, and it comes from the NASA website.]

Hubble Telescope

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Happy 27th birthday to the LTEE!

The title says it all:  today is the 27th birthday of the long-term evolution experiment (LTEE) with E. coli.

Well, the title doesn’t really say everything. I also want to give thanks to the many people—not to mention the trillions of bacteria—who have made it possible for the LTEE to keep on going and giving.

So thank you to all of the students, postdocs, and colleagues with whom I’ve collaborated on this project. There are too many to list here, but you will find their names on the papers that have come from the LTEE. I’ll call out just two, on this occasion, for special thanks. Dom Schneider has been an amazingly talented and generous collaborator for so many years—in fact, our first co-authored paper on the LTEE dates back to 1999. And Neerja Hajela has worked with me for 20 years now, and she is the most organized, dedicated, and all-around wonderful technician and lab manager that one could ever have.

Special thanks, too, to Madeleine Lenski, who has tolerated my long-term affair with the LTEE, and who wisely advised me to keep it going on one or two occasions when I was looking in other directions.

[The image below shows the abstract from the first paper on the LTEE, which appeared in The American Naturalist in 1991. It is reproduced here under the doctrine of fair use.  Some of the conclusions have changed a bit as the LTEE has had more time and we’ve gathered more data—that’s science!]

Abstract 1991 LTEE

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