The Next Time

As we continue to fight the current covid pandemic caused by the SARS-CoV-2 virus, it’s not too early to begin thinking about the next pandemic.  I’ve been mulling this over for a while, and I was prompted to write this post by a twitter thread from Michael Baym.

Michael wrote about some work that he and Kaylee Mueller started, early in the pandemic, to develop a rapid colorimetric assay for covid.  They decided to curtail their work, however, when the personal risk of continuing to work in the lab seemed too great. But Michael is now wisely looking ahead, thinking about what science can do to respond even more quickly to the next pandemic.

Last February, as most of the world was just waking up to the threat posed by covid, I wrote a post with words of wisdom for pandemic preparedness. The words were written by a former Secretary of the US Department of Health and Human Services, Michael O. Leavitt, in 2007, who at that time was especially concerned about the potential for an influenza pandemic. He said: “Everything we do before a pandemic will seem alarmist. Everything we do after a pandemic will seem inadequate. This is the dilemma we face, but it should not stop us from doing what we can to prepare.”

So congratulations, and thanks, to Michael and all the others who are looking ahead. But really, all of us need to look and think ahead, using our hearts as well as our minds. 

Almost exactly a year ago, I was very worried about how hard this country would be hit by the pandemic.  I wrote:  “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 suggested that a number of epidemiological and sociopolitical issues would contribute to the United States being especially hard hit by the pandemic.  Among the former, “China’s outbreak started from a single point source in Wuhan … 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 …”  Among the latter, “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 … 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.”

My worries about the next pandemic have been leaning to the problems of social division and disregard for evidence.  As terrible as this pandemic has been, the next one could be worse … even much worse.  How will people react if the next pandemic is 10 times more deadly than covid?  What if the next outbreak causes disproportionate mortality in kids or young adults?  Would the (mostly) right-wing denialists still refuse masks? Would anti-vaxxers (on the left & right) still oppose vaccination?

So, Michael Baym is right to be thinking ahead, as was Michael O. Leavitt. As a nation, we need to commit resources to support science (including the basic sciences that lead to breakthroughs in medicine) as well as our often neglected public-health system.  But we also need to find ways to come together as people, to overcome the sometimes willful ignorance, and to discuss things in a meaningful, non-conspiratorial way. 

Science and public-health workers can only do so much. The rest is up to all of us to protect ourselves, our families, and our communities from covid … and from the next pandemic … and from ourselves.

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They’re back!

They’re back! After a six-month interruption, Devin Lake restarted the long-term evolution experiment and the 12 LTEE lines from the 73,000-generation freezer samples. Now the bacteria are back in their home-sweet-homes: Erlenmeyer flasks with DM25 medium and the shaking incubator set to 37C.

We’re keeping the lab at very low occupancy, and using masks and physical distancing when more than one person is present in a room) until this damn SARS-CoV-2 pandemic is under control.

MSU also has a spit-based surveillence program in place for those entering campus buildings. Each sample is split, and then put into two pools for PCR testing. With each individual’s sample split into two pools, the testing can identify which individual in any reaction that proves to be positive is the source of the virus. That person is then notified and told to isolate and get a definitive diagnostic test.

[Both photos below courtesy of Devin Lake]

Six Months

It’s been six months since I closed the lab, and temporarily suspended experiments including the LTEE, due to the SARS-CoV-2 pandemic.

The failure to contain this epidemic, especially here in the United States, is truly shocking and sad.

Still, we’ve gotten a lot done. Two superb dissertations completed by Nkrumah Grant and Kyle Card. Several excellent papers submitted, and more on the way. Everyone in the lab remains healthy, and in my own family as well, even as we know that many others have suffered illness and losses.

And please, everyone: Wear your mask and maintain social distancing to protect not only yourself and your own family, but also your community and beyond.

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!

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.

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.

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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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.]