On Microbial Individuality

This post is written by UI postdoc Jessica Lee

Selfie with scanners

I’m writing this blog post in hopes of convincing you to see every microbial cell as a unique individual. It’s a big ask, because microbes are numerous, and even card-carrying microbe lovers have a tendency to think of them as populations rather than as single cells. I’ve been guilty of the same thing; it’s only since I started working as a postdoc in the Marx Lab at UI that I’ve started to appreciate microbial individuality. And doing so has also forced me out of my comfort zone and into using tools to study microbes in unusual ways—an experience that I’m thrilled to share with you.

Much of microbiology has been built on the assumption that if two bacterial cells have the same genes and live in the same environment, they’ll behave in the same way. This assumption stems partly from necessity: it’s hard to study a single cell, so for most of the history of bacteriology, we’ve studied microbes by growing billions of genetically identical (“clonal”) cells in flasks and quantifying their bulk properties– for instance, measuring how fast the mass of the population doubles, rather than watching individual cells divide. We’ve long known that this is an oversimplification, but it’s a very effective oversimplification, one that has often allowed us to make predictions with stunning accuracy.

Except… sometimes even a clonal population of bacteria contains some cells insist on doing their own thing. One well-known example of such “phenotypic heterogeneity” is microbial persistence in the face of antibiotic-induced death. When a sensitive population of bacteria is treated with bacteriocidal antibiotics, most of them die at a rate that is so predictable it can be used to model precisely how much drug and how much exposure time are necessary to eliminate the population. But amid all the antibiotic carnage, we often find a small minority of cells that, nevertheless, persist.

The researchers who first examined this phenomenon by observing individual cells in action found that persister-type cells die slowly because they were previously growing slowly: they just happen to be a minority sub-population that hasn’t been actively reproducing. In general, that’s not a great strategy for a bacterium, because the whole point of being a bacterium is to make more bacteria. But it does turn out to be a good strategy if a pulse of antibiotics suddenly shows up, because antibiotics are more harmful to growing cells, so non-growing cells are able to withstand exposure longer. The most remarkable thing is that persistence is, ironically, transient—a cell can pop in and out of the persistent state, and doesn’t give its offspring any special ability to withstand antibiotics. (This makes it fundamentally different from the genetic antibiotic resistance that is a growing problem in hospitals today.) We even have evidence that this phenotypic diversity can be a useful evolutionary strategy, allowing the microbial population to “hedge its bets” by keeping a few non-growing cells on hand even while most are reproducing normally, ensuring that there will be a some survivalists ready to hunker down and wait it out a pulse of antibiotics should strike.

What does all of this have to do with my own research? Phenotypic heterogeneity seems to play a role in the way bacteria deal with a variety of different stresses, and in the Marx Lab, we study a very specific stressor: formaldehyde. Our model organism, Methylobacterium extorquens, is able to eat methanol, but when it does it produces formaldehyde as a metabolic intermediate. And somehow it manages the constant presence of that toxin quite well. We’ve recently observed some examples of phenotypic heterogeneity in M. extorquens populations, both when dealing with formaldehyde in its environment and when simply initiating methanol growth, and we’re curious to find out whether heterogeneity might be a survival strategy, or at least provide a clue about the mechanisms that M. extorquens uses to manage formaldehyde stress.

Colony growth trajectories. Each line represents an individual bacterial colony and its increase in size over time. Red lines and blue lines are two different genotypes; even within the blue genotype, there is marked variability in the amount of time it takes a colony to start growing (less so in the red genotype).

There are a few ways to observe differences among individual bacterial cells, many of them involving very fancy equipment, but one of my favorite methods is one of the simplest: looking at bacterial colonies on petri dishes. Of course, a colony is a dense mass of millions of cells, but each colony began as a single cell, so if you watch a lot of colonies, you can learn something about the variation in the single cells that started those colonies. For instance, we’ve found that if we stress cells with formaldehyde and then plate them out onto a formaldehyde-free petri dish to recover, some pop up right away and others take a long time to start growing. The distribution of colony arisal times may therefore give us some information about the growth state of the bacteria when they were stressed, or the nature of the cellular damage from the formaldehyde.

Timecourse of images of colonies developing on a culture plate over several days.

What’s more, you can observe an awful lot of colonies as they grow if you place your petri dishes on a flatbed photo scanner and scan them every hour! For real—I’m talking about the kind of scanner you can buy at your local office supply store. I’ve fallen in love with this method not only because it generates really cool data, but also because building it has been uncommonly fun. There doesn’t yet exist a company (that I’m aware of) that sells petri-dish scanners, though there are other labs who have built these systems and happily offer guidance. I’m a biologist who started in on this project all geared up for pipetting and plating and culturing, certainly not expecting that I’d find myself setting up a custom scanner array—routing cables galore through our lab ceiling, troubleshooting power supply issues, calibrating temperature probes, and writing code for image analysis. It has been a fantastic growing experience not only for my bacteria but for me as well. I’ve also been amazed at the enthusiasm and generosity of friends and strangers—biologists and non—who have offered their help. I’m hoping that this project will not only further our understanding of microbial biology in a new direction, but continue pushing me in a new direction too.

Stressed-out bacteria form colonies at different times; the ones that recover fastest end up being the biggest.

Balaban, N.Q., Merrin, J., Chait, R., Kowalik, L., and Leibler, S. (2004). Bacterial persistence as a phenotypic switch. Science 305, 1622–1625.

Ackermann, M. (2015). A functional perspective on phenotypic heterogeneity in microorganisms. Nat Rev Micro 13, 497–508.

Levin-Reisman, I., Fridman, O., and Balaban, N.Q. (2014). ScanLag: High-throughput Quantification of Colony Growth and Lag Time. J Vis Exp.

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The evolution of code is like the evolution of DNA nanotechnology

This post is written by UI faculty Peter Allen

I’m Peter Allen, a professor of Chemistry at the University of Idaho. I use DNA nanotechnology to build tiny things like autonomous nanomachines. DNA is more than genes and heredity. When I tell people that I work with DNA, they often ask me what species I got my DNA from. I didn’t get my DNA from any living creature. I invented the sequence. I synthesized the molecule. It doesn’t correspond to a gene or to heredity or to biology at all. The DNA I made is just a chemical. It has interesting chemical properties like no other molecule.

As a chemical, DNA has rules that I can understand. With a few exceptions, DNA has four components that bind together in a specific pattern: adenosine (A) binds to thymidine (T); guanine (G) binds to cytosine (C). Synthetic DNA can be made that has any sequence of these components. When DNA is synthesized, it only has half of the double helix. A piece of DNA can be made with a sequence like AATGC. That piece of DNA wants to bind to another piece of DNA with the reverse-complement sequence, GCATT. When they bind together, they make the spiral we’re all familiar with.

With that simple rule set, people have built some amazing and complex things. People have folded DNA into 2D and 3D shapes. People have used DNA to manipulate light. Remarkable reactions including catalysts and amplifiers have been built using these base pairing rules. I am particularly inspired by the work of Yin et al. I adapted the Yin designs to make a DNA nanomachine that walked around on microscopic particles. As they walked, they created a signal I could see with my eyes.

This technological field is evolving like Linux does: through the sharing of code. I think that’s weird. DNA is the physical embodiment of biological evolution, but this synthetic DNA is evolving in our brains and computers. Building a structure by hand is too hard, so software is used to design the DNA interactions that will create a structure. That software is often open source. That software also evolves in the same way that Linux distributions evolve.

DNA nanotechnology is a strange mix of literal evolution and digital/social evolution. The open source software used to create DNA origami (like CADnano) presumably will evolve like Linux. If you look at the Linux timeline, it looks like a phylogenetic tree. This is more than a passing resemblance: Linux has almost literally evolved. Linux is an open source operating system. Anyone can change the code. Programmers make changes in their personal copy. That’s like a mutation. If those changes are good, they might be adopted by the official community or added to the “distribution” (a shared package of official code). That’s selection and reproduction. Sometimes, a change is very radical. The community splits and creates a second distribution entirely which then evolves separately. That’s speciation. This process of gradual change with occasional splits in the lineage (and occasional extinctions) is the same kind of process that creates phylogenetic trees in nature.

DNA nanotechnology software evolution will depend on the kinds of rules we discover. If we can inform this software with new data, maybe we can help this software do more. DNA, by itself, can make some interesting structures aside from the double helix. For instance, DNA can make a folded “quadruplex” structure if it has enough G’s in the sequence. But what about DNA when it is mixed with other things like proteins?

Aptamers are DNA that has evolved to bind a target molecule like a protein. By repeatedly amplifying and collecting DNA that binds to some target molecule (and removing non-binding DNA), one can select strong binders. Aptamers are like synthetic antibodies. Aptamers can be used for all kinds of things. If a scientist or physician needs to determine if a specific biomolecule is present, it can be detected with an aptamer. This can be especially powerful when combined with DNA nanotechnology. Some enterprising folks even took aptamer binding and used it to create a signal that could be amplified using DNA circuits.

How will DNA design software evolve to incorporate aptamer binding? I suspect that there are patterns in aptamer sequences. I suspect that there are rules for what kinds of sequences aptamers come from. One of the projects we are working on in the Allen lab is to get deep sequence information from aptamer selections. Maybe with that data in hand, we can start to tease out some new rules and artificial selection and evolution can inform digital evolution.

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National Alliance for Broader Impacts Guiding Principles

The National Alliance for Broader Impacts has recently put out a “Guiding Principles and Questions for National Science Foundation Proposals” informational PDF.


It provides great info if you’re thinking of broader impacts for a NSF proposal as well as if you’re thinking about broader impacts for any other purpose!

There is also a push for NSF review panels to use the NABI handout as a guideline when reviewing grants, so it’s worth checking out!




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Kay Holekamp receives the MSU Graduate School Outstanding Faculty Mentor Award

Congratulations to Kay Holekamp for being the inaugural recipient of the MSU Graduate School Outstanding Faculty Mentor Award!

See the entire letter to Kay from Judith Stoddart, Interim Dean and Associate Provost for Graduate Education, below highlighting the admirable qualities that won Kay the award.

The selection committee (which included a college associate dean, a graduate program director, associate and assistant deans from the Graduate School, and a graduate student) was impressed by the nominating letter written by 5 of your doctoral students and a recent PhD detailing the professional and personal impact you have had on their lives.  They talked about the ways that you sustain a supportive and collaborative atmosphere within your lab from the time prospective students e-mail you through their post-graduate work, about your “thoughtful and exhaustive feedback” on professional and personal topics, and about how you have made connections that have enabled them to be joint authors with scientists at other institutions.  They remarked on the ways that you model mentoring for them and then encourage them to practice it by including undergraduates in all stages of their research.  They also indicated that your mentorship extends beyond the academic community, including, e.g.,  children’s book authors who visited your field site in Kenya last year.

Your chair noted the fact that you mentor not only your own students, but those of others.  You have done this informally as well as in formal roles such as graduate director of ZOL/IBIO and EEBB.  You also developed and continue to offer the Integrative Biology graduate student professional development course.

Your chair describes your attitude toward students as “incredibly generous.”  Your students were even more emphatic, writing “While the marks of a superb scientist are quickly identifiable on their CV, the marks of a superb mentor are far less obvious.  Here, Kay’s distinguishing habits include a respect for all persons and never-ending willingness to help.  Such actions are not only time-consuming, but they are also selfless . . . . Kay engages in such mentorship activities—both in the traditional sense within academia as well as in non-academic settings–routinely and without a second thought.”

In honor of your receipt of the award, the Graduate School will provide you with $3000 to support mentoring activities.  Please be in touch with me about the kinds of activities you would like to support.  We can provide funding in this budget year, defer all of it, or split the amount.  You will also receive an engraved plaque in honor of the award.

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Kalyanmoy Deb, BEACON’s Koenig Endowed Chair Professor, has crossed 100,000 citations

Screen Shot 2017-04-20 at 1.15.52 PM
Kalyanmoy Deb, Koenig Endowed Chair Professor of Electrical and Computer Engineering and a BEACON member, has crossed 100,000 citation mark according to Google Scholar (https://scholar.google.com/citations?user=paTAXiIAAAAJ&hl=en). He is one of the two faculty members in the College of Engineering, and one among four at MSU to achieve this recognition according to Google Scholar (https://scholar.google.com/citations?hl=en&view_op=search_authors&mauthors=Michigan+State+University). His h-index is 102, indicating 102 of his publications have received at least 102 citations each. For more information about his research in evolutionary computation and optimization, visit http://www.egr.msu.edu/~kdeb or his COIN lab website http://www.coin-laboratory.com.

Kalyan’s and his work have been seen repeatedly on our blog

Pareto Improvement of Pareto-Based Multi-Objective Evolutionary Algorithms (October 5, 2016)
BEACON at GECCO 2016 (August 18, 2016)
BEACON Researchers at Work: Evolution makes software adaptive (March 10, 2014)
BEACON Researchers at Work: What’s a Genetic Algorithm? (October 28, 2013)
Kalyanmoy Deb receives the World Academy of Sciences Prize in Engineering Sciences (October 18, 2013)
BEACON’s Kalyanmoy Deb receives honorary doctorate (September 18, 2013)
BEACON’s Kalyanmoy Deb wins Cajastur Mamdani Prize for Soft Computing (December 8, 2011)

Some of Kalyan’s most cited work includes…

K. Deb, A. Pratap, S. Agarwal, and T. Meyarivan (2002). A fast and elitist multiobjective genetic algorithm: NSGA-II. IEEE transactions on evolutionary computation, volume 6, no. 2, pages 182-197. (23,553 Citations)

This is most likely the highest-cited paper in evolutionary computation. This paper suggested an evolutionary multi-objective optimization (EMO) algorithm, which parameter-less, modular, and computationally fast. NSGA-II boosted the research and application of EMO and is implemented in a number of commercial optimization softwares.

N Srinivas and K Deb. (1995). Muiltiobjective optimization using nondominated sorting in genetic algorithms. Evolutionary computation, volume 2, no. 3, pages 221-248. (6,003 Citations)

The NSGA procedure proposed in this paper was the precursor of NSGA-II and is one of the three first EMO methods which demonstrated the suitability of evolutionary algorithms for finding multiple Pareto-optimal solutions for a multi-objective optimization problem.

Zitzler, K. Deb, and L Thiele. (1999). Comparison of multiobjective evolutionary algorithms: Empirical results. Evolutionary computation, volume 8, no. 2, pages 173-195. (4,349 Citations).

This paper proposed a six-problem test suite for multi-objective optimization, which are largely known as ZDT problems today. The paper also compared a number of existing EMO methods for solving ZDT test problems. ZDT problems allowed EMO researchers to evaluate their algorithms in a systematic manner.

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James Foster Honored at EvoStar Conference in Amsterdam

Informal presentation at Conference Banquet Thursday, April 20, 2017.

On Thursday, April 20, 2017, BEACON’s Lead at University of Idaho, Prof. James Foster, was honored by SPECIES, the professional organization that sponsors the annual EvoStar Conference, at its the 20th annual Evostar Conference, this year held in Amsterdam. He was one of two members honored for their lifetime contributions, winning the 2017 EvoCROC Award for Most Outstanding Contribution to Evolutionary Computation in Europe. While this award is generally given to Europeans, Foster’s record of contributions to the field and his participation and leadership in the EuroGP Conference, one of EvoStar’s four conferences, won him this recognition. The other awardee was Prof. Gusz Eiben of the Free University of Amsterdam. On hand to help award the prizes was BEACON’s Prof. Wolfgang Banzhaf, the John R. Koza Endowed Chair in Genetic Programming, and Treasurer of SPECIES, BEACON Director Erik Goodman and Idaho BEACONites Terry Soule and Barrie Robison.

More formal presentation at EvoStar Awards and Closing Session, Friday, April 21, 2017. Left to right (standing) are: Ernesto Costa, Penousal Machado, Marc Schoenauer, Wolfgang Banzhaf, James Foster, Anna Esparcia, Gusz Eiben and Jennifer Willies.

James Foster and Gusz Eiben, the 2017 winners of the EvoCROC Award for Most Outstanding Contribution to EC in Europe.

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BEACON-sponsored “Business for Scientists” course at UI

With supplemental funding from NSF, BEACON is co-sponsoring a week-long “Business for Scientists” course offered at the University of Idaho, May 22-26. This course is designed to help junior faculty, postdocs, and scientific staff run their research program like a successful business (see the flyer for additional details). The course is free to attend, and there is travel and accommodation support available from BEACON. You must RSVP by emailing ibest@nulluidaho.edu by May 5. If you would like to apply for BEACON travel funds to this course, please contact Danielle Whittaker.

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Why We March

This post is written by NCA&T faculty Joe Graves

On the 13th of April, Nature, the publication of the British Association for Advancement of Science (and founded by Charles Darwin) endorsed the March for Science (https://www.marchforscience.com/ ). Nature is one of over 100 professional scientific organization that have endorsed the march, including the American Association for the Advancement of Science (AAAS), the Union of Concerned Scientists, the European Geosciences Union, American Chemical Society, and others. There are now over 500 satellite marches planned (including all the BEACON partner sites: Lansing, MI; Pullman WA and Moscow, ID; Seattle, WA; and Austin, TX). As a member of the coordinating committee for March for Science (Greensboro) I would like to extend to all BEACONites a personal invitation to join us on April 22nd, 2017 as we march to inform the public concerning the crucial importance of supporting both the scientific method of reasoning and enterprise for the health of our nation and world.

This march is about much more than recent cuts to science funding. Having said that, the projected cuts are stark. Last month, the American Institute of Biological Sciences (AIBS) released an analysis of the Trump administration’s FY 2018 budget’s impact on scientific research and education2. The Trump budget would increase military spending by 10% to approximately $639 billion dollars. To pay for this increase cuts are projected to occur for the Environmental Protection Agency (-30%), Department of Agriculture (-29%), Department of Energy offices of Science (-16%) and to the National Institutes of Health (-18%).   The National Oceanic and Atmospheric Administration grant programs would be cut by $250 million. These programs support coastal and marine research and education. The Sea Grant program, which provides research, education, and extension services, would be eliminated.

At a time when the world is in dire need of advances in scientific research such cuts could have disastrous consequences. Therefore it is imperative to march to demonstrate our passion for science and sound a call to support and safeguard the scientific community. The incredible and immediate outpouring of support for the marches has made clear that these concerns are also shared by the support of hundreds of thousands of people around the world.

It is also crucial to reject the mischaracterization of science as a partisan issue. Despite the popular conception that most scientists are political “liberals”, scientists have always displayed ideological views that cross the political spectrum. Let us not forget that Wernher Von Braun (who utilized Jewish slave labor to build his rockets) and Shiro Ichii (microbiologist head of Unit 761 that deployed anthrax and bubonic plague weapons on Chinese civilians) were scientists. In addition both of these men had their war crimes ignored because the technology they developed was desired by the United States after World War II had ended. Indeed, as I have mentioned in earlier posts, science as an enterprise and many scientists have often been ardent supporters of unjust and inhumane social policies. Indeed, despots of all varieties and flavors are more than happy to support scientific research and products that are consistent with their own political agenda. The US Supreme Court utilized the science of the racial polygenists (Louis Agassiz and Samuel Morton) to justify their decision that Dred Scott or any other Negro had “no rights that a white man was bound to respect” in 1857 (Graves 2005) and about 50 years later would deny that same racial science in not recognizing the right to citizenship of Bhagat Singh Thind under the Caucasian requirement (Bean and Lee 2009). Just as today there is no argument made by policy makers against the science involved in producing and deploying the “mother of all bombs”, GBU-43/B used in Afghanistan last week (http://www.cnn.com/2017/04/13/politics/afghanistan-isis-moab-bomb/ ), while at the same time they have no problem denying the physics and chemistry behind anthropogenic climate change.

What scientists agree on is the power of our method, dubbed “the scientific method” to provide the world utilitarian knowledge about nature. Evolutionary science is among those fields most fertile in that regard. As early as the 1940’s evolutionary biologists like Th. Dobzhansky warned the world concerning the danger resulting from the unchecked use of pesticides and antibiotics. At the time, these warnings were summarily ignored (e.g. Van den Bosch 1978), yet it is now recognized that we may be entering the “post-antibiotic” phase of human civilization (http://www.bbc.com/news/health-34857015). In a more strange case, scientists including evolutionary biologists utilized knowledge of past global level extinction events, warned the world concerning the fallacy of “limited nuclear war” (Ehrlich et al. 1983). These warnings have gone unheeded, as the United States still maintains a nuclear arsenal capable of killing the world’s population eight times over (although it can be argued that the movement to build more powerful non-nuclear engines of mass destruction is evidence that these warnings have been taken seriously).

The mistaken view that scientists are political liberals has given some of our current policymakers permission to reject overwhelming evidence, especially when it contradicts their specific political agenda or the profit motives of those who put them into office.  Nowhere is this more obvious than in the current attack on climate science. For example, Dr. Michael Mann warned congress of the dangers of this phenomenon over 14 years ago. Since that time he has been sued, forced to testify in front of congress, been investigated, and received death threats (Mann and Toles 2016).

So in reality, it is not that those in power do not accept science, it is that they “cherry pick” which science they will accept and support. The Republican Party has been historically anti-evolution mainly because much of its political base (evangelical Christians) is anti-evolution. It is now anti-climate science because much of its financial support comes from industries that want to continue developing and burning fossil fuels. Days after taking office, the Trump Administration initiated a poll asking American manufacturers how to best cut federal regulations to make it easier for companies to get their projects approved. There were 168 comments received and ½ were directed at the Environmental Protection Agency and 1/5 toward the Department of Labor. Some examples of these comments include:

BP wants to make it easier to drill for oil and gas in the Gulf of Mexico by reducing how often companies must renew their leases.

A trade association representing the pavement industry wants to preclude the U.S. Geological Survey from conducting what the group says is “advocacy research” into the environmental impact of coal tar. The Pavement Coatings Technology Council says this research could limit what it uses to seal parking lots and driveways.

Source: https://www.washingtonpost.com/politics/epa-emerges-as-major-target-after-trump-solicits-policy-advice-from-industry/2017/04/16/87a8a55a-205d-11e7-ad74-3a742a6e93a7_story.html?utm_term=.6f6e0eee7198&wpisrc=al_alert-COMBO-politics%252Bnation&wpmk=1

Clearly in the case of both of these comments, scientific principles and scientists working for these corporations are involved in both drilling for oil and gas, and developing the sealing technologies mentioned.

Thus I do not see the rejection of science as the most critical and urgent matter to be addressed by this march. More it is scientists themselves recognizing that science and its applications have always been political. In this light, it is time for people who support scientific research and evidence-based policies for the public good to take a stand and be counted. Many who take the podium this week will be not be willing to make the distinctions I have discussed above. They will be parroting time worn platitudes and trying to find the lowest common denominator concerning how and why science should be supported. On the contrary, I will be speaking to the need for scientists to rise up against those who are applying our craft to support the corporate greed that is driving the wanton destruction of our environment and against those who are applying our craft to maintain social injustice. I will call scientists to imagine a different way of working for humanity.

Indeed, for this to happen we as scientists will have to look inwards. We will have to ask questions about why we do what we do, and how the science enterprise is in the main still a Eurocentric, male-dominated, heterosexist project. If we can manage this conversation productively we will move towards the day when our community will be more representative of all socially-defined races and ethnicities, religions, gender identities, sexual orientations, abilities, socioeconomic backgrounds, political perspectives, and nationalities. And with this diversity, we will be more capable of implementing scientific research that actually does better the lives of all those who now depend on us more than ever before.


Bean, F.dD. and Lee, J. Plus ḉa Change. . .? Multiraciality and the Dynamics of Race Relations in the United States, Journal of Social Issues 65(1):205—209, 2009.

Ehrlich, P.R., Harte, J., Harwell, M.A., Raven, P.H., et al., Long-term biological consequences of nuclear war, Science 222: 1293—3000, 1983.

Graves, J.L., The Emperor’s New Clothes: Biological Theories of Race at the Millennium, (New Brunswick, NJ: Rutgers U. Press), 2005.

Mann, M. and Toles, T., The Madhouse Effect: How Climate Change Denial is Threatening Our Planet, Destroying Our Politics, and Driving Us Crazy (New York: Columbia University Press), 2016.

Van den Bosch, R., The Pesticide Conspiracy, (Berkeley, CA: U. California Press), 1978.


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Teeny tiny creepy crawlies: the phage in your backyard

This post is written by MSU postdoc Sarah Doore

When I was little, my dad would often take me around the backyard to hunt for bugs. Spiders—which are not bugs, but little me didn’t care about taxonomy at the time—were my favorite. Upon discovery, I could have spent hours watching arthropods just do their arthropod things. Each hunt was its own exciting adventure. What would I find today? Where would the best spiders be? The best caterpillars? Should I check plants or should I try looking under rocks?

Dr. Doore in the field gathering samples, ca. 1989

Four year-old me didn’t know she was laying the foundation for a future in science, but my bug-hunting days would end up shaping my interests in both expected and unexpected ways. In undergrad, I thought I was going to be an entomology major and study bugs—or rather, insects, as I eventually learned the distinction between the types of arthropods—forever. Well, instead of entomology, I ultimately got a PhD in microbiology. My dissertation research was on bacteriophages, or phage, which are viruses that infect bacteria. These weren’t the bugs my younger self had in mind, but phage tail fibers sort of look like spider legs, so…close enough?

I recently joined Kristin Parent’s lab at MSU as a BEACON postdoc. We’re both phage enthusiasts, and one day we were lamenting the dearth of phages that infect Shigella flexneri, the bacterial species our lab works with. We decided to remedy this. Could we find more Shigella phages by hunting for them in the environment?

“Phage hunting” has recently gained a significant following, with multiple universities contributing to phage discovery projects. The biggest of these is the Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) program, which is an alliance of over a hundred universities. Each university has a two-semester phage hunting program, where undergraduate students isolate and characterize bacteriophages they find in the environment. While Michigan State University is not (yet?) a member of this alliance, we wanted to give phage hunting a try. Besides, with an estimated 1031 phage particles in the world, we’re only beginning to scratch the surface of bacteriophage diversity. The more phage we find, the merrier!

Bacteriophage infecting a bacterium: our lab’s interpretation with Giant Microbes (left); under an electron microscope (right). Scale bar is 50nm.

Every fall, Dr. Parent teaches a section in the graduate course Integrative Microbial Biology (MMG801) here at MSU. While SEA-PHAGES focuses on undergraduate courses, we wanted to start on a very small scale to test our methods and gauge students’ responses before scaling up. The SEA-PHAGES program also spans two semesters, whereas our section would last just a few weeks. We asked groups of 2-3 students each to dig into the literature, develop hypotheses about where they were most likely to find phage, and come up with some possible methods to isolate them. They would be screening their samples on three types of Enterobacteria: Salmonella enterica, Escherichia coli, and Shigella flexneri.

A lot of those bacteria are found in the gut (hence the entero in Enterobacteria), which means they can also be found in poop. Because of this, most groups went for locations that were…less than sanitary. One group grabbed river sediment near a wastewater treatment plant, two groups took water from the Red Cedar River where it flows through campus, a couple groups went to locations where they thought they would find livestock or waterfowl manure, one group scraped some biofilm off a water buoy in the river, and one group decided to swab an apple from the student union.

Upon retrieving their chosen material, the groups then processed their samples in our lab. The students put some of their sample on agar plates or in liquid cultures of bacteria. The next day we checked the plates for the formation of plaques, which are small clearings where phage have killed all the bacterial cells in the region. We also checked the liquid cultures to see which ones had cleared: another indication of bacterial death.

Out of seven groups, the four that sampled in or around the river were all successful. Between those groups, the class isolated a total of 18 distinct phages! Much to our lab’s joy, most of those bacteriophages infect Shigella flexneri. Surprisingly few infected S. enterica or E. coli, which was the complete opposite of what we expected. Most previously-described enteric phages infect Salmonella or E. coli, which is why we were hoping to find some Shigella phages in the first place. Maybe Shigella phages just aren’t that popular or were assumed to be uncommon in the environment, so people haven’t been looking. (For more on the topic of fortuitous-but-unexpected results, I recommend reading Frederick Grinnell’s chapter on “Luck in Science” from The Scientific Attitude. The section on “controlled sloppiness” was particularly relevant to me.)

An agar plate with bacteria (white/opaque portion) and plaques (small dark circles). This is phage Jawnski from the University of Pittsburgh. Sarah often sees plaques like this when she closes her eyes after a long day in the lab.

We kept the students updated with our findings while we characterized their phages. We sent them pictures of their phage under the electron microscope. We tested the phages’ host ranges and sequenced their genomes, which we’re still in the process of analyzing. We see some unique properties of these Shigella phages, and we hope to submit a paper on our findings this summer. At the end of the semester, students’ reviews were very positive: “very interesting lecture and cool project!” and “I REALLY loved the fact that the homework assignment was hands-on field and benchwork.” There was only one criticism: they wish it had lasted longer!

Now we’re working to get similar modules into undergraduate courses here at MSU and in other schools. Phage hunting can be fun for everyone, and hopefully the thrill of discovery can get more students interested in science. So although this isn’t the kind of hunting my younger self ever would have thought about, I think she’s okay with it. The experience of getting your hands dirty, wondering whether to check under rocks (or buoys!), thinking about what you might find where…these are all the ingredients of science. As long as there are new phages to be uncovered and new questions to be asked and answered, the hunt will continue.

References and resources:

Hendrix R.W. et al. (1999) Evolutionary relationships among diverse bacteriophages and prophages: all the world’s a phage. Proc. Nat. Acad. Sci. USA 96:2192-2197.

Grinell, Frederick. The Scientific Attitude. New York: Guilford Publ. 1992. Print.

Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science: https://seaphages.org/


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Join the conversation: links between communication and cooperation in bacteria

This post is written by UI postdoc Eric Bruger (twitter: @elbruger13)

Eric’s first (and less antagonistic) conversation with the stubborn tot mentioned herein.

We are used to thinking of ourselves as helpful beings, and humans are comparatively more cooperative in relation to many other species. The ability to cooperate is a major reason humans have been able to colonize much of the globe and form the complex societies we live in today. But the occurrence of cooperative behavior is far from a foregone conclusion: evolutionary theory tells us as much [1], and anyone who has tried to get a two-year-old child out the door can probably relate to the following recent exchange with my daughter:

“Ella, can you get your shoes on?”
“We have to go to the store.”
“No store.”
“We need to get in the car so we can go to the store.”
“No car.”
“Don’t you want to go outside?”
“No go outside.”
“Please, Ella…”
(wanders off and starts playing with stuffed Cookie Monster instead)

As with winning that negotiation with a stubborn child (when that is even possible), the incentives to cooperate must be correctly aligned, whether that be directed more by benefits for cooperating or costs for opting to not cooperate. What may not be as apparent is that there are countless examples of cooperative interactions within and between other species in nature. This even extends to microscopic organisms that we generally consider to be non-cognitive (although see [2 & 3] for further discussion). Well known among microbiologists, but interesting nonetheless, you do not need to have a brain to cooperate with others!

Bioluminescence provides one of nature’s more amazing (biological) light shows, here available in liquid flask or solid petri plate formats!

During my doctoral research in the Waters Lab at Michigan State University, a central question that interested me was how cooperation among bacteria might be preserved and how it was impacted by their ability to communicate. My favorite system to examine these questions was the bacterium Vibrio harveyi, a well-studied organism known for its ability to carry out a form of communication termed “quorum sensing” (QS) and also the ability to produce light, or bioluminesce. V. harveyi cells produce the enzyme luciferase, which catalyzes a reaction between its substrate and oxygen, and emits a resulting bluish hue of light. The light emitted by one cell alone is not visible to the naked eye, but it is visible when cells are present in dense clusters or in cultures where billions of cells are present, forming a detectable phenotype. The light response is regulated by QS and is only fully activated after levels of bacterially-produced chemical signals exceed a critical concentration – this is affected by prevailing environmental conditions and often driven by local cell densities.

Because QS controls the expression of a large number of V. harveyi‘s genes, and up-regulates many more than it down-regulates, activating QS is a cost burden on participating bacterial cells. So what’s the upside of having QS, and why wouldn’t these bacteria just evolve to save on this cost by not not quorum sensing? This phenomena of defectors has actually been observed in many experimental, clinical, and natural samples, lending support to the idea that defecting is increasing the fitness of these cells. However, defecting can come at other costs. The inability to sense and respond to signal levels could have negative effects when there are important correlated traits like resistance to toxic chemicals, in varying environments, in conditions where interactions between members of the same type – cooperator or defector – more often than with other types, or in the case that QS-regulated traits provide large fitness benefits.

One of the benefits QS provides for V. harveyi is the ability to grow and produce higher yields on complex protein substrates like casein compared to non-QS defectors.

The traits turned on by QS includes the production of extracellular proteases at high cell densities. These enzymes are cooperative public goods, as the benefits generated by them can be shared amongst the entire surrounding community. Growth on complex growth substrates like casein, which requires breakdown for cells to fully access, is aided by the production of these proteases. Some of our work [4] examined competitive outcomes between cooperator and defector strains in casein media. The results provided a demonstration that, while unregulated cooperation was susceptible to exploitation by defectors, QS-regulation provided a degree of protection against this and allowed cooperators to persist in the presence of defectors. This was true even in large well-mixed populations, where theory predicts they should be most susceptible to such exploits.

To test whether or not QS could stabilize cooperative behaviors over longer timescales, we conducted a 2,000 generation experimental evolution with replicate populations of Vibrio harveyi. Replicate populations of either the wild type (WT) strain that possesses a functional QS system and cooperates depending on signal levels, or a mutant strain that unconditionally cooperates regardless of external inputs like cell density, were passaged in a casein media. We found that non-QS defectors evolved from both strain backgrounds, but the resulting dynamics of the defectors were very different depending on the strain from which they evolve. From the unconditional cooperator strain, defectors rapidly evolved and uniformly swept those populations. These defectors exhibit a nonluminescent phenotype resulting from no QS activation of luciferase production. Alternatively, in nearly all WT populations, bioluminescent clones persisted at significant levels for the entirety of the experiment. Ongoing sequencing work is pursuing the molecular bases of these changes to determine whether parallel or diverse evolutionary paths are followed in our experimental populations.

Together, the competition and experimental evolution results we have observed show that bacterial chemical communication, in the form of QS, allows V. harveyi to maintain greater levels of cooperation within mixed populations and may be required to allow cooperation to persist [5]. QS appears to be playing a critical role that may be shifting the balance of costs and benefits in cooperation’s favor. So keep up the conversation, and good things might just happen – just don’t count on that two-year-old to agree with you!


  1. West, S. A., Griffin, A. S., Gardner, A., & Diggle, S. P. (2006). Social evolution theory for microorganisms. Nature Reviews Microbiology, 4(8), 597-607.
  2. Lyon, P. (2015). The cognitive cell: bacterial behavior reconsidered. Frontiers in microbiology, 6, 264.
  3. Shapiro, J. A. (2007). Bacteria are small but not stupid: cognition, natural genetic engineering and socio-bacteriology. Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences, 38(4), 807-819.
  4. Bruger, E. L., & Waters, C. M. (2016). Bacterial quorum sensing stabilizes cooperation by optimizing growth strategies. Applied and Environmental Microbiology, 82(22), 6498-6506.
  5. Czárán, T., & Hoekstra, R. F. (2009). Microbial communication, cooperation and cheating: quorum sensing drives the evolution of cooperation in bacteria.PloS One, 4(8), e6655.
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