Five More Years

The E. coli long-term evolution experiment (LTEE) began in 1988, and it has run for over 32 years with only occasional interruptions. The latest interruption, of course, reflects the temporary closure of my lab during the ongoing coronavirus pandemic. Fortunately, one of the advantages of working with bacteria is that we can freeze population samples and later revive them, which will allow us to resume their daily propagation when it is prudent to do so.  Indeed, we’ve frozen samples of all 12 populations throughout the LTEE’s history, allowing “time travel” to measure and analyze their fitness trajectories, genome evolution, historical contingencies, and more.

Even as the experiment is on ice, the lab team continues to analyze recently collected data, prepare papers that report their findings, and make plans for future work. Their analyses use data collected from the LTEE itself, as well as from various experiments spun off from the LTEE.  Nkrumah Grant is writing up analyses of genomic and phenotypic aspects of metabolic evolution in the LTEE populations.  Kyle Card is examining genome sequences for evidence of historical contingencies that influence the evolution of antibiotic resistance. Zachary Blount is comparing the evolution of new populations propagated in citrate-only versus citrate + glucose media. Minako Izutsu is examining the effects of population size on the genetic targets of selection, while Devin Lake is performing numerical simulations to understand the effects of population size on the dynamics of adaptive evolution.  So everyone remains busy and engaged in science, even with the lab temporarily closed.

Today, I’m excited to announce two new developments.  First, the National Science Foundation (NSF) has renewed the grant that supports the LTEE for the next 5 years. This grant enables the continued propagation of the LTEE lines, the storage of frozen samples, and some core analyses of the evolving populations. The grant is funded through the NSF’s Long Term Research in Environmental Biology (LTREB) Program, which “supports the generation of extended time series of data to address important questions in evolutionary biology, ecology, and ecosystem science.” Thank you to the reviewers and program officers for their endorsement of our research, and to the American public and policy-makers for supporting the NSF’s mission “to promote the progress of science.”

Second, Jeff Barrick joins me as co-PI on this grant for the next 5 years, and I expect he will be the lead PI after that period.  In fact, Jeff and his team will take over the daily propagation of the LTEE populations and storage of the sample collection even before then. I’m not planning to retire during the coming grant period. Instead, this transfer of responsibility is intended to ensure that the LTEE remains in good hands for decades to come. In the meantime, Jeff’s group will conduct some analyses of the LTEE lines even before they take over the daily responsibilities, while my team will continue working on the lines after the handoff occurs.

Several years ago I wrote about the qualifications of scientists who would lead the LTEE into the future: “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 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.”

Jeff is an outstanding young scientist with all of these attributes. Two years ago he was promoted to Associate Professor with tenure in the Department of Molecular Biosciences at the University of Texas at Austin.  He has expertise in multiple areas relevant to the LTEE including evolution, microbiology, genomics, bioinformatics, biochemistry, molecular biology, and synthetic biology. He directs a substantial team of technicians, postdocs, and graduate students, which will provide ample coverage for the daily LTEE transfers (including weekends and holidays). Last but not least, Jeff has participated in the LTEE and made many contributions to it including:

  • Participated in propagating the LTEE lines and related activities while he was a postdoc in my lab from 2006 to 2010.
  • Authored many papers using samples from the LTEE, including almost all of them that have analyzed genome sequences as well as several recent papers examining the genetic underpinnings of the ability to use citrate that evolved in one lineage.
  • Developed the open-source breseq computational pipeline for comprehensively identifying mutations that distinguish ancestral and evolved genomes.

Someone might reasonably ask if the LTEE will work in the same way when it is moved to another site. The answer is yes: the environment is simple and defined, so it is readily reproduced. Indeed, I moved the LTEE from UC-Irvine to MSU many years ago, the lab has moved between buildings here at MSU, and we’ve shared strains with scientists at many other institutions, where measurements and inferences have been satisfactorily reproducible. As an additional check, Jeff’s team at UT-Austin ran a set of the competition assays that we use to measure the relative fitness of evolved and ancestral bacteria, and we compared the new data to data that we had previously obtained here at MSU. The two datasets agreed well, in line with the inherent measurement noise in assessing relative fitness. Fitness is the most integrative measure of performance of the LTEE populations, and it is potentially sensitive to subtle differences in conditions. These results provide further evidence that, when the time comes, the LTEE can continue its journey of adaptation and innovation in its new home.

Evolve, LTEE, evolve!

LTEE flasks repeating

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Time to restart the LTEE, this virus be damned

The LTEE ran for over 32 years and more than 73,000 generations, without missing a beat. Then this stupid coronavirus came along and made me shut down the lab and stop the experiment. Well, I think it’s high time for everyone to return to the lab and get back to work.

We’ve wasted a hell of a lot of time here.  The LTEE lines were frozen on March 9th.  That’s 23 days ago, for crying out loud.  Do you know how many generations have been lost?  With 100-fold daily dilution and regrowth, that’s ~6.7 generations per day.  So we’ve already lost over 150 generations. And with 12 populations that’s a net loss of more than 1,800 generations.

Another way of looking at it is that each population produces around half a billion new cells each day.  So that’s 23 x 12 x 500,000,000 cells that went missing. You get the picture, that’s a sh*t-load (a technical term for those of us who study E. coli) of baby bacteria that never got born!

I’ve gotten in enough trouble already with a certain crowd for our claim to have observed evolution. If they find out we’ve denied these adorable baby bacteria their existence, there’s no telling what letters they might send me.

Plus, speaking as a scientist, I have this premonition that something really big would have happened during those missing generations. I’ve been expecting them to evolve the ability to produce palladium from citrate. They could then use the palladium for cold fusion, which would surely get some attention. Stupid virus!

Heigh-ho, heigh-ho, it’s back to work I go.  I sure hope you have a nice day at home.

Calendar April

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Do you teach a biology lab that has been disrupted by the coronavirus outbreak?

The following is a guest post written by my colleague, Rob Pennock.

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Do you teach a biology lab that has been disrupted by the coronavirus outbreak?  If so, you may want to consider using the Avida-ED experimental evolution platform as a virtual replacement.

Avida-ED logo

To limit the spread of the coronavirus, many colleages and universities have suspended in-person classes, and instructors have had to scramble to replace them with on-line instruction.  Biology faculty who teach laboratory-based courses find it especially difficult or impossible to do their planned lab exercises.  Avida-ED may provide a valuable substitute for some classes.

Avida-ED is an award-winning educational application developed at Michigan State University for undergraduate biology courses. It is aimed at helping students learn about evolution and the scientific method by allowing them to design and perform actual experiments to test hypotheses about evolutionary mechanisms using evolving digital organisms.  Funded by the NSF, Avida-ED is the educational version of a model system used by researchers to perform evolution experiments–including many that have been published in leading scientific journals (see some examples below).  Avida-ED is not a simulation, but an instantiation of the evolutionary mechanisms and process that allows for real experiments.  Avida-ED produces copious data that can be analyzed within the application or exported for statistical analysis.  Avida-ED has been used in classrooms across the country and around the world for over a decade.

Here are more reasons that Avida-ED may provide a useful, quick replacement for your lab:

  • Avida-ED is free.
  • Avida-ED requires no special registration or configuration.
  • Avida-ED is accessible on-line and runs locally in your web browser.
  • The user-friendly interface requires little technical training to use.
  • It includes ready-to-use exercises to teach a variety of evolutionary concepts.
  • It can also be used for open-ended labs where students design and perform their own experiments.
  • It can be used to teach principles of experimental design and scientific method.

See the Avida-ED web site for:

  • Link to the Avida-ED application launch page.
  • Model exercises (under the Curriculum link).
  • The Avida-ED lab book.
  • Quick start user manual.
  • Background information about digital evolution.
  • Articles about Avida-ED, including effectiveness studies.

The Avida-ED team is working to provide instructional videos for the core exercises from train-the-trainer workshops that we have offered in previous summers, where we teach faculty how to use the software in their own classes.  We can also provide instructor support materials for some exercises offline for certified instructors.  A mirror of the Avida-ED site is available in case the primary site goes down.

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Lenski, R. E., C. Ofria, T. C. Collier, and C. Adami.  1999.  Genome complexity, robustness and genetic interactions in digital organisms.  Nature 400: 661-664.

Wilke, C. O., J. Wang, C. Ofria, R. E. Lenski, and C. Adami.  2001.  Evolution of digital organisms at high mutation rates leads to survival of the flattest.  Nature 412: 331-333.

Lenski, R. E., C. Ofria, R. T. Pennock, and C. Adami.  2003.  The evolutionary origin of complex features.  Nature 423: 139-144.

Ofria, C., and C. O. Wilke.  2004.  Avida: A software platform for research in computational evolutionary biology.  Artificial Life 10: 191-229.

Chow, S. S., C. O. Wilke, C. Ofria, R. E. Lenski, and C. Adami.  2004.  Adaptive radiation from resource competition in digital organisms.  Science 305: 84-86.

Ostrowski, E. A., C. Ofria, and R. E. Lenski.  2007.  Ecological specialization and adaptive decay in digital organisms.  American Naturalist 169: E1-E20.

Clune, J., R. T. Pennock, C. Ofria, and R. E. Lenski.  2012.  Ontogeny tends to recapitulate phylogeny in digital organisms.  American Naturalist 180: E54-E63.

Goldsby, H. J., A. Dornhaus, B. Kerr, and C. Ofria.  Task-switching costs promote the evolution of division of labor and shifts in individuality.  Proceedings of the National Academy of Sciences, USA 109: 13686-13691.

Covert, A. W. III, R. E. Lenski, C. O. Wilke, and C. Ofria.  2013.  Experiments on the role of deleterious mutations as stepping stones in adaptive evolution.  Proceedings of the National Academy of Sciences, USA 110: E3171-E3178.

Goldsby, H. J., D. B. Knoester, C. Ofria, and B. Kerr.  2014.  The evolutionary origin of somatic cells under the dirty work hypothesis.  PLoS Biology 12: e1001858.

Fortuna, M. A., L. Zaman, C. Ofria, and A. Wagner.  2017.  The genotype-phenotype map of an evolving digital organism.  PLoS Computational Biology 13: e1005414.

Canino-Koning, R., M. J. Wiser, and C. Ofria.  2019.  Fluctuating environments select for short-term phenotypic variation leading to long-term exploration.  PLoS Computational Biology 15: e1006445.

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If You’re Not Scared, You’re Not Paying Attention

Attention Earthlings:  If you’re not scared by the coronavirus pandemic that is now accelerating around your planet, then you’re not paying attention. The time for action—both personal and collective—is now.

As Harvard epidemiologist Marc Lipsitch has said, this pandemic is not an existential crisis for humanity–our species will survive. However, most of us have lived in a blessed time and place compared to most of humanity, one that has been largely free of deadly infections. The actions we take now—immediately—will be critical to restore that safety that we took for granted.

I think it is entirely possible, maybe even likely, that Europe will get hit harder by the coronavirus than China has been hit, and the US may get hit even harder than Europe.

I have two reasons for these scenarios:

1/ Epidemiology:  China’s outbreak started from a single point source in Wuhan. Europe got multiple seeds from many travelers, which then started many separate transmission chains. The US, meanwhile, has gotten many independent seeds both from China and from Europe … hundreds or even thousands of smoldering embers at first, most growing unseen and uncontained to vastly larger numbers now, and still growing exponentially—roughly doubling every week. We’ve had severely limited testing, and many of those cases with few if any symptoms are especially hard to find, making it exceptionally hard to trace contacts and contain the infection with self-isolation and quarantine.

2/ Sociopolitical: China has deep social roots, a respect for expert knowledge, and (like it or not) rigid enforcement of rules. Europe has, at least, the respect for expert knowledge. But here in the US, we have deep social divisions, widespread skepticism of expertise (often fed by those divisions), an extremely complex political landscape with federal, state, & municipal layers of government (also polarized by the social divisions), and many independent-minded people who are inclined to disregard advice and instructions—a wonderful attitude some of the time, but an exceptionally dangerous attitude during a pandemic. (I apologize for these over-generalizations; they are only intended to call attention to some of the particular challenges that we face here in the US.)

I certainly hope I’m wrong that the USA will be especially hard hit by COVID19. However, we must face up to the challenges—both epidemiological and sociopolitical—that the coronavirus pandemic brings to us individually and collectively. Take care everyone.

Attention Parents of high-school and university students who are interested in parties and/or bars, especially with many schools now closed to in-class instruction:  It’s time for heart-to-heart discussions with your kids—not about “the birds and the bees” but about “the bugs and disease”—for everyone’s sake.

ADDED:  Here’s a great image for parents to share with their high-school and college-age kids about the critical role they can play by social distancing.  It was made by John Drazan.

Why low-risk should social-distancing

 

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Meetings Large and Small

In this post, I will explain why it is important not only that we cancel large conferences and other events, we should also curtail medium and even small gatherings that are non-essential.

Joshua Weitz has done a great service by explaining how the probability that one or more participants in an event is infected scales with the size of the gathering. In brief, even when the vast majority of people are not infected, the chance that somebody is infected goes up as the number of participants gets larger. I think most people are also now coming to grips with the rapid growth of this outbreak, which means that a meeting with relatively low risk today might be a very bad idea a month from now.

But does this mean that medium-sized and small events can proceed without worry? No. Let me explain why even these events should be reduced to the bare minimum that are essential. Most of my readers are fellow scientists, so what follows is cast in the language of conferences and departmental seminars—but hopefully others can relate these to similarly sized gatherings in their own lives.

Ok, to begin. You’re very pleased to hear that the conference you had planned to attend next month was canceled. With 10,000 attendees, and with infections doubling every week, it was clearly smart to cancel such a large conference. But your departmental research seminar is attended by only 100 people. Surely that can safely continue, right?

If only your department had a seminar, and if it was a one-time event, then sure, why not. However, there are 25 other departments around the country in your field of study alone, and each of the departments has planned 4 weekly talks over the coming month.  Seen in that light, it’s like that large conference of 10,000 — except that its 25 x 4 = 100 events with 100 attendees each. In other words, there are 10,000 potential transmissions of the viral infection.

In general, as event sizes get larger (more participants), the frequency and number of those events becomes smaller.  I don’t have data to back this up (maybe somebody does), but I’d bet that the number of small gatherings increases even faster than the number of participants falls off.  For example, for every conference of 10,000 people, I expect there are even more than 100 meetings of 100 people.

Therefore, reducing non-essential gatherings of all sizes should be part of our individual and collective efforts at social distancing. It’s no fun, I know. But it’s one of the best ways we can ward off this beast of a virus, and thereby protect our colleagues, our friends and families, and our communities.

[This image shows the actor Rowan Atkinson (aka Mr. Bean). It is used here under the doctrine of fair use.]

Mr Bean

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Canary in the Coal Mine?

The news just came out that South Dakota — South Dakota! — has 5 presumptive cases of SARS-CoV-2 infections, including 1 death.  South Dakota has lovely people and places, but it’s not exactly the center of the universe, or even of the midwest.  It has ~885,000 people in total … roughly 0.3% of the US population.  So a simple extrapolation to ~330 million people would imply something like 1,800 infections over the entire USA.

There’s good news and bad news.  Good news: there weren’t 5 cases reported in North Dakota, which has an even lower proportion of the US population.

All the rest is bad news.  We’re assuming all potential infections have been tested and discovered.  We’re also looking in the rear-view mirror, time-wise. In most cases, it takes a few weeks for an infection to lead to death (when it does, which fortunately is not usually the case). Maybe a week or so to develop symptoms that would lead to someone being tested.  So let’s call it a week.  Well, this virus typically doubles in a week or so.  So 1,800 infections a week ago (ones that have become symptomatic today) implies ~3,600 infections at present in the USA as a whole.

Well then, maybe it’s a cluster in an old-folks home, like the one near Seattle?  Tragic, if so, but young folks might shrug it off.  Nope: 1 person in her 30s, 2 in their 40s, 1 in his 50s, and 1 (the deceased) in his 60s.

Well, maybe at least they’re all part of one cluster, like the community outbreak in the Seattle area.  So maybe it could be viewed as a single case, not 5 separate transmission chains.  Nope!  There are reportedly no known connections among these cases, which were all in different counties in South Dakota.

Well, maybe it’s because South Dakota is a major travel center, with people coming and going from all over the world?  Come on now: I guess you’re not from around here.

ADDED: It is also possible that South Dakota’s testing is flawed. We can hope.  I think the samples will be re-tested by the CDC.  That said, I’m seeing as high or higher estimates of the numbers of infections in the USA from other evidence that has nothing to do with these South Dakota cases.

ADDED: Let me be very clear. Given (i) the lack of adequate testing performed in the USA to date, (ii) the fact that South Dakota is not a travel hub, (iii) the facts of this situation as reported in the news, and (iv) the various assumptions in my calculations above, my estimate of 3,600 infections in the USA as of today is very conservative. The actual number could be 10 times higher, or even more.  See these calculations from infectious-disease modeler Alex Perkins (Notre Dame University). He estimates that there are now several thousand new infections per day in the USA, with perhaps 30,000 to 50,000 to date. And whatever the number, it is likely to double every week or so for some time.

[Location of South Dakota in United States, from Wikipedia page with attribution.]

South Dakota in US

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We Interrupt This Experiment

Today I made the decision to close the lab and temporarily suspend our experiments, including the LTEE, in light of the expanding SARS-CoV-2 outbreak.

I started to say it was a difficult decision, but really it was not all that difficult.  Several considerations led me to this decision.

1/ The SARS-CoV-2 outbreak appears to be taking off in many countries, including the USA, despite the substantial containment that has been orchestrated in Wuhan and elsewhere in China.

2/ The absence of evidence of any local cases is not as comforting as it might be, given the near-absence of testing here and in most of the USA.

3/ MSU students just returned from spring break today.  Some of the superb undergrads who work in my lab went to places that have confirmed cases. None of the places they went are among the locations with intense outbreaks, but the confirmed cases in at least one location have grown noticeably in the past week. They also flew on planes to and from their vacations.

4/ As a team, we’re connected not only to one another, but also to people who are health-care workers and others with increased vulnerabilities to infections. (Not to mention that I’m over 60 …) When you think about it, pretty much everyone has those connections.

5/ We’re very lucky because our work is easy to stop and re-start. Our study organisms can be frozen away and revived whenever we see fit.  In the meantime, everyone has classes to take, papers to read and write, data to analyze, etc.  And a little extra time, hopefully, to reflect on and maintain the health and well-being of our friends, families, and selves.  So, we will all be busy, but doing things a bit differently than we had planned.

6/ As we freeze away the long-term lines, the lab notebook will record:  “On this day, the LTEE was temporarily halted and frozen down for the coronavirus pandemic of 2020.”

Hopefully, some future historian of science will look back on today’s entry and say: “What the hell was that all about?”

Freezing LTEE for SARS

[Devin Lake putting the LTEE populations into the ultra-low freezer, where they will stay until they are called back into action … evolution in action.]

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