‘MOOC it, MOOC it’? – My impressions of an online Coursera course in Epidemics.

By Jonas Waldenström

I just finished a course in epidemics at Penn State University. But without setting my foot on campus, or, in fact USA! And guess what, I didn’t miss a single lecture! Sounds weird? Thing is, this was not an ordinary course; this was a MOOC – the latest development in distance learning. And it was great! But more on that later.

We live in an ongoing digital and technical revolution – just compare everyday life today with how it was ten, or twenty years ago. The change is not linear; rather it is a series of punctuated shifts, where each new wonder gadget push the field to a new plateau. For instance, back in 1999 when I worked in northern Nigeria it was virtually impossible to phone home. In the bigger cities you could pay for a call via landlines, but in the area where we worked the closest phone was 10 hours away, across the sand dunes. A few years later mobile phones were everywhere, and Internet cafes were popping up on the posh streets. In fact, these days, you often have better connection between Nigeria and Sweden, than between Kalmar and Öland…

The hallmark of an obsolete technique

The hallmark of an obsolete technique

Another example, although more linear, is the ever-faster computer processors, or the speed at which you can sequence DNA. When I started my PhD, the art of drawing figures by hand, in ink, for publications was still remembered. And during my first year I was extremely happy if I managed to run 10 sequences (of roughly 500 bp each) over night on the capillary sequencer! Now you can print a gun in 3D, or sequence a genome over night. At least a microbial genome, and a very simple gun. But still, who would have believed this 20 year ago?

Education, however, has evolved at a slower pace, even after the onset of computers. Yes, some guy invented PowerPoint in 1987 and sold it to Microsoft, thereby turning a bad lecture into a worse, but more colorful lecture. (Actually, the ‘internets’ tell me they were two guys: Robert Gaskins and Dennis Austin, and that they both think their creation has sometimes turned into an abomination.) Otherwise the key concepts of a lecture have remained the same for many centuries. Teaching is primarily occurring here and now, in a room of varying size at a campus. Teacher goes in, does his/her thing and hopefully the students become enthusiastic, interact and learn. A familiar process for all of us, unless you drop out of school at the age of seven. A good lecture can change your purpose of life. On the other hand, a bad lecture can be akin to torture and be remembered for far too long.

The future of education as seen in 1905

The future of education as seen in 1905

The question now is whether this is about to change? At least, for the first time it seems as technology is there, or nearly there, to allow things to be done differently. And this is where the MOOC – the Massive Online Open Courses – comes in to play. Education for the masses, free and online. Some believe this way of teaching will make education democratic and open it for everyone, not only the fortunate who by smartness or rich parents study at the prestigious universities. Via a connection to the Internet it is now possible to enroll in courses on a vast number of subjects. A smorgasbord of education. Through sites as Coursera, the disparate courses can be collected into a degree; tailored and individual-based degrees.

So what about the epidemics MOOC? Truly, it was a magnificent course! The team of teachers was like a NHL team of only seriously talented scientists: Dr. Marcel Salathé, Dr. Ottar N. Bjornstad, Dr. Rachel A. Smith, Dr. Mary L. Poss, Dr. David P. Hughes, Dr. Peter Hudson, Dr. Matthew Ferrari, and Dr. Andrew Read. And it was indeed a massive course, even for a MOOC! One figure that was mentioned was 27,000 enrolled students! One year I gave my course, with a rather similar content, to 6 students – that tells you of the potential outreach a well-managed online course can have compared to a campus course at a small university.

A screen shot of Dr Andrew Read in action.

A screen shot of Dr Andrew Read in action.

A MOOC, or any type of distance learning, is as good as the teachers are, and the time and resources put in by the university. The Epidemics MOOC was certainly an extremely good example, where it was evident that they wanted to do something more than the ordinary, set a new standard even. However, even if the course was beautifully made and stuffed with interesting lectures, I reckon that there must have been a massive drop out of students. Not because the course was too advanced, but because it is so easy to procrastinate things to a point where you have several weeks of lectures to digest. A human fallacy, I’d say. Also, I guess that a significant fractions of students, and perhaps over-represented among those that finished it, were folks like me. Folks that already have a degree, or even work with the subject. But that doesn’t matter too much after all – if only 10% of the students made it all the way, it still means that a staggering 2,700 people now are acquainted with the basics of epidemiology!

In case Marcel Salathé (or any of the other teachers) reads this little piece, I’d like to end with some reflections of the course:

You understood your audience. Most people that are enrolled in distance education are already busy. If you have a day job you don’t have all the time in the world. You want things to be condensed, edited and thoroughly thought through. In my case I watched the videos when my youngest daughter was napping – which isn’t forever, I can tell you. Instead of long lectures there were several short (5 – 9 min each); short enough to maintain focus, and long enough to say something important. Well done!

We could see you! I love the fact that the videos were not uploaded powerpoints with voice-over. These were actual lectures recorded in studio, where the lecturer looked into the camera. Instead of the ppt, the main notes were highlighted via cartoons appearing together with the talker. That’s smart!

I could rewind, skip, press forward, and even adjust the speed of the talks. The possibility to watch lectures when you want to is great, of course. And that you can download them and watch when you are offline too. I also liked the speed button. The Andrew Read NZ dialect required a 0.75 speed setting, while Ottar Bjornstad and Mary Poss were best enjoyed at a 1.25 pace. Splendid idea!

Ask us anything. The idea of picking questions from the study forums and have group discussion among the faculty was an excellent idea. And a possibility to pick up recent events like flu and MERS. I liked this, good move.

The heterogeneity of students was a problem, at least for discussions. A central idea is that the platform should stimulate discussion via online forums. For this course it was expected that the student engaged in at least 10 posts to earn credits. However, with 27,000 students enrolled the level of comments was often more Facebookish than intellectual. Perhaps it would have been good to add a few explanatory lectures (like a week zero) describing the very basics (such as what a virus really is).

With that said, I really enjoyed the course! Whether the MOOCs will change education as we know it is still an open question though. We will see what the future brings! Or to paraphrase Reel 2 Real: MOOC it, MOOC it!

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Travel the world – can antibiotic resistant bacteria hitchhike with migratory birds?

By Jonas Waldenström

800px-Seasons1.svgThe beauty of a planet rotating around a slightly tilted axis (23.5 % to the orbital plane, to be exact) is the variation this brings to the intensity of the sunlight that hits the ground. It gives rise to predictable seasonal changes, at our high latitudes equal to a blooming spring, a warm summer, a foggy and mild autumn, and a frosty winter. The tilted axis also means that when it is dark and cold Sweden, it is sunny and lovely on the other side of the globe. Or in other words: when my kids make snow angels in the yard, the penguins rear their chicks under the austral sun.

A large number of animals, in particular birds, but also bats, antelopes, and even insects, utilize the shifts in climate and migrate to make most of the boom of ephemeral resources made available during the warmer seasons. Go to the food, reproduce, raise the offspring, and then pull back to chill-out at lower latitudes during the non-breeding season. A related phenomenon has evolved in some human populations – it is now common that British, German and Swedish people undertake annual migratory movements to Spain. Unlike the other animals mention above, the human movements mainly involve the post-reproductive life-stages. Hordes of well-off elderly now bask in the sun and marinate their livers in cheap red wine. Senescence in the sun.

Basking in the sun

Basking in the sun

A reason why our elderly go to Spain, and not onwards to Morocco, or east to Turkey is the apparent similarities to home. It is different in Spain, yes, but still rather similar to Bavaria, Sussex or Jönköping – just warmer and more vibrant. But not too dangerous, or too vibrant. You can trust the water to be (moderately) clean, and you can eat the food without worrying too much about infections. A prophylactic intake of wine and a diet consisting of 50% canned foodstuffs from home and you are unlikely to succumb to nasty disease.

In epidemiology, we know for certain that travel brings you in contact with disease-causing organisms. When we travel we expose ourselves to pathogens to which our immune systems lack experience, and therefore fail to take swift actions. This is nothing new – this was the fait of the native Indians in South America facing the import of pathogens such as smallpox and whooping cough from invading conquistadores. And in tropical Africa, the Yellow Fever took a large toll of the missionaries sent to christen the heathens; and those fortunate to survive had to endure repeated spells of malaria fevers, and gastrointestinal unpleasantness. Today, prophylaxis and vaccines make us more prepared, but disease risks are a constant worry for the traveller even in our time. And when we get back from our travels we may carry bugs with us and cause secondary cases back at home. In the last weeks we have seen cases of MERS coronavirus associated with haji in Mecca in Arabic countries and Europe. In many gastrointestinal bacterial infections we see a higher degree of antibiotic resistance in travel-associated cases than in domestic cases. Simply, what goes around comes around – and travelling stirs the pot to a boil.

Furthermore, what we put in the pot – the meat and the apples – is highly important. Very little on your dinner plate was grown in your backyard, in fact the ingredients that make up the dish may have travelled half around the globe before being eaten by you. Our food animals are amplifying hosts for many pathogens that cause human infections. The shear numbers of animal involved, the transportation of animals and products, and the frequent use of antibiotics in the food production industry make an additional potent driving force for antibiotic resistance evolution.

On top of this, in the last decade a question whether wild birds can act as flying intercontinental carriers of resistant bacteria has emerged, again and again. The idea can be summarized as follows: If a bird picks up a resistant bug during the non-breeding period, and that bacterium becomes established in the gut, there is a chance that the bacterium could be disseminated along the migratory route all the way to the breeding grounds. Given the state of the world, where for instance there is a marked south-to-north gradient in bacterial resistance problems in Europe, and likewise between South and North America, bird migration can be associated with words like ‘risk’ and ‘threats’. Birds as flying missiles, or pathogen arks.

Did the pathogens fit on the Ark?

Did the pathogens fit on the Ark?

Seemingly elegant, this hypothesis suffers from a number of limitations. First, birds need to be colonized by the nasty bacteria in the first place. Then the bacteria need to be maintained in the gut of the bird for a considerable time, allowing the bird and the bug to move during migration. Once migrated, the bacteria need to be shed in such a manner that they find their way to humans, or more likely our domestic food animals, and then end up on our plate. A long way to go for a microorganism.

Our research group is addressing such questions. The first step is to thoroughly survey the occurrence of antibiotic resistant bacteria in wild birds. This process has going on for a few years, and although there is room for many, many more studies we do know something by now. First, antibiotic resistant bacteria are everywhere, literally everywhere – from the Arctic tundra to the vicinity of the Antarctic research bases. Wildlife is exposed to resistant bacteria and some birds, such as gulls and crows, tend to often carry resistant bugs. Second, we know from genotyping studies that the same types of resistance markers occur in bacteria both from human/food animals and in wild birds. Thus, there is an exchange between sources, likely heavily tilted towards a dissemination from anthropogenic sources to wildlife (rather than the opposite) and it seems most strongly occurring in specific bird species that are in close proximity to humans and food animals.

The most recent study from our group on this subject was published a few weeks ago. The study focused on a bird species that qualify for all of the check points that make a species a possible resistance disseminator culprit: the Franklin’s gull Leucophaeus pipixan. This species breeds in North America, in shallow lakes on the prairies between USA and Canada, but spend the non-breeding season all the way down in southern South America. In Peru and Chile it is common to see thousands of Franklin’s gulls at river mouths on the Pacific coast. And in these rivers the collected wastewater from millions of people are discharged. Thus the gulls find themselves in a habitat that potentially is full of unwanted antibiotic resistant microbes.

Gaviotas de Franclin at Con-con. Photo Jonas Bonnedahl

Gaviotas de Franclin at Con-con. Photo Jonas Bonnedahl

The team visited the Aconcagua and the Bio-Bio rivers in central Chile, where the water met the sea at Concón and Talcahuano, respectively. At these gorgeous sand beaches they sampled Franklin’s gulls. Samples were also collected from 49 healthy human volunteers from the city of San Antonio. Back in Sweden, the samples were cultivated for the presence of Escherichia coli, the most commonly used indicator bacterium in antibiotic research. Randomly collected isolates were then tested against a panel of 10 different antibiotics to measure the degree of acquired resistance. The original samples were also screened for a specific class of resistance mechanisms called extended spectrum beta-lactamases. Bacteria that produce these ESBL enzymes are resistant to a range of lactam antibiotics. ESBL resistance is an emerging problem all over the world, causing suffering and premature deaths.

The resistance profiles from the 267 avian E. coli were similar to that of human samples, with moderate resistance to ampicillin (10.1 %), tetracycline (8.2 %), and streptomycin (6.0 %). Only nitrofurantoin displayed full susceptibility in all samples; all others were in the range of 0.5 – 5 %. However, looking at ESBL in the samples, the gull sample had a prevalence of 30 %, compared to 12 % in the human sample. Not only were there loads of ESBL-positive birds, the ESBL variants were dominated by blaCTX-M-1 and blaCTX-M -15 genotypes that has been extensively described in E. coli causing human infections. Also a multilocus sequence typing of the bacteria showed connections to bacterial genotypes common in infections.

Thus, on the warm sands of Chile sits Franklin’s gulls and enjoy the austral summer. In their intestines they carry resistant bugs with the same genotypes that can cause  infections in humans. Remains to show if the birds can carry these bacteria to the US, or whether carriage is short-lived and more a product of the local environment.

Link to the article here:

Hernandez J, Johansson A, Stedt J, Bengtsson S, Porczak A, et al. (2013) Characterization and Comparison of Extended-Spectrum β-Lactamase (ESBL) Resistance Genotypes and Population Structure of Escherichia coli Isolated from Franklin’s Gulls (Leucophaeus pipixcan) and Humans in Chile. PLoS ONE 8(9): e76150. doi:10.1371/journal.pone.0076150

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How bats in Peru change our view of flu (and it rhymes!)

By Jonas Waldenström

I am the real Bat Man and here to bite y'all

I am the real Bat Man and here to bite y’all

One of the major news in the virology community last year was the publication in PNAS describing a completely new influenza A virus. In line with the taxonomy traditionally used for influenza viruses it got the name H17N10, illustrating that it possessed novel hemagglutinin (H17) and neuraminidase variants (N10). However, it wasn’t the numbers that was the ground breaking news, it was the fact that the virus was detected in a Central American bat, and not in a bird. A tropical bat is very far from the ‘normal’ diversity of influenza A viruses seen in wetland birds and waterfowl. Although bats and ducks both have wings, in evolutionary terms they separate a very, very long time ago in the age of dinosaurs. In fact, there are more differences than similarities between bats and gulls in ecology, physiology and aspects of cellular biology. Hence, the bat flu was a remarkable observation. A real shaker. In one sweep, the whole flu field needed to come with terms that not all viruses are bird viruses.

The initial findings also hinted that the first bat influenza virus was unlikely to be alone. An influenza-iceberg, of sorts, made up of fluffy, winged mammals. This week, a first follow-up was published in PLOS Pathogens. A crew of (mainly American) scientists analyzed samples from bats sampled in the Amazonian parts of Peru in 2010, collected as part of CDC’s tropical pathogen surveys. In total, 114 individuals of 18 bat species were taken out from the freezers and different sample types were screened with a molecular method designed to broadly pick-up the RNA of any influenza A virus. They got one hit from a fecal sample in a single bat! A lucky shot at the Tivoli, given the low sample size. Prompted by this, the authors brought in the big machinery and sequenced the totality of the genetic material in the samples from this poor, long-dead bat and used bioinformatic tools to resolve the genome of the virus that had infected its intestines. When bit by bit was added it became clear that it was indeed a completely new influenza A virus, very different from avian viruses, and similar, but still distinctly different from the earlier H17N10 bat virus. And the name? H18N11 of course!

Please take a close look at the figure below. It shows the phylogenetic relationships of each of the influenza A virus’ eight RNA segments – in black are all ‘non-bat viruses’ and in red the two new bat viruses H17N10 and H18N11. For all the segments coding for ‘internal’ proteins, i.e. those involved in the polymerase machinery or the structural properties of the virus, you see that the two bat viruses are always found in a neat little red outgroup. This signals a long evolution away from other known influenza A viruses. It is a little prematurely to say exactly how long, but the branch lengths indicate that this happened a long time ago.

Phylogenetic trees for the 8 different IAV segements, see http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003657

Phylogenetic trees for the 8 different IAV segements, see http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003657

Now look at the hemagglutinin and the neuraminidase trees (HA and NA, respectively). The same pattern is repeated for the NA, but not the HA. In fact, the two novel hemagglutinins are nested within avian hemagglutinins. How can we interpret this? At first this doesn’t make any sense, but one has to remember that influenza viruses don’t evolve in the same way you or me, trees, shrimps or ferns do. Influenza viruses can reassort, meaning that if two viruses of different origin infect the same cell the different RNA segments can be put in new combinations in the resulting virions. Imagine two decks of cards being shuffled, one red and one black, and that each virion randomly consists of a draw of card from the combined shuffled deck, sometimes red, sometimes black, and sometimes mixed.  This is a rapid way in which new variants can arise, and a reason behind the genesis of pandemic flu in humans.

Returning to the bats, it seems that bat and avian viruses have met in a not too distant evolutionary past, and that a HA variant have sailed into the bat influenza gene pool. It will be interesting to see how the picture changes when more bat viruses are sequenced. Has there been one reassortment event, followed by drift and a subsequent separation into H17 and H18? Or, has there been many? Are there, perhaps, avian H17 and H18 to be found in South American birds? What about bats in North America, Europe, Africa and Asia?

One thing we can be sure of is that there are more viruses waiting to be detected and described. One sign of this comes from the current paper. The authors used the sequenced genomes to construct recombinant HA and NA molecules (using fancy virologist tricks) and used these to build assays (ELISAs) where bat sera could be screened for antibodies against the new HA and NA variants. Where the molecular screening yielded one positive bat, the serology approach found 55 of 110 bats showing signs of having been infected with flu earlier in life. This clearly indicates that influenza viruses are widespread in Peruvian bats, and likely in other parts of the world too. Moreover, they found cases of bats with antibodies to one of the recombinant HA or NA, but not to the other, suggesting that are more combinations of HA/NA to be found.

Finally, and perhaps the most interestingly of all results was that the hemagglutinin of bat influenza viruses does not to behave in the same way as avian hemagglutinins. When a virus is to infect a cell it needs the hemagglutinin protein to serve as a key, docking with a sialic acid receptor – the lock – on the cell. If the key and the lock don’t fit infection will not occur. For instance, a major division between human flu and avian flu is the preferred conformation of a galactose residue on the sialic acid receptors. This little difference makes it hard for avian viruses to infect humans, and vice versa. But with bat viruses it seems sialic acid receptors are not used at all! Instead bat HA uses an unknown receptor for cell entry. Holy Moses!

More to follow shortly, I suppose. Major obstacle at present is the lack of a culturing method for bat influenza viruses. Neither cell lines nor eggs have worked so far. Without the means to grow the virus it is very tricky to study it. But there are many clever virologists out there, so it is likely not too far away.

But I still prefer feathers to fur, and will stick with ducks.

Links to articles:

Tong S, Zhu X, Li Y, Shi M, Zhang J, et al. (2013) New World Bats Harbor Diverse Influenza A Viruses. PLoS Pathog 9(10): e1003657. doi:10.1371/journal.ppat.1003657

Tong S, Li Y, Rivailler P, Conrardy C, Castillo DA, et al. (2012) A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci USA 109: 4269–4274.