Even the most lethal pathogens we know of don’t kill every single infected individual.¹. Sometimes this is because the pathogen that infects the person is relatively weak. Sometimes it’s because the dose was low. And sometimes it’s because of something intrinsic to the patient. Some people are genetically resistant to HIV, because they have a mutated receptor, for example.

The opposite is also true. Sometimes people are more intrinsically susceptible to a pathogen. That became terribly clear during the AIDS epidemic, when quite innocuous agents started killing people, but there are probably many, many natural genetic variants that make us susceptible to some pathogens, just as some make us resistant. When epidemiologists look for “risk factors” that increase mortality or disease severity, this is part of the information they’re trying to tease out, in a rather crude way Sorting this out is part of the goal of the whole personalized medicine movement.

A fascinating example was just documented in MMWR. ² Here a researcher was working with a genetically modified form of Black Plague bacteria (Yersinia pestis). This bacteria should have been harmless, because it had had its ability to grab iron from the host removed. ³. But the researcher became infected, and died, of an infection with the weakened strain.

We now learn that this was probably because the researcher had his own genetic mutation, hereditary hematochromatosis, which leads to increased levels of iron in the blood. He may⁴ have been uniquely susceptible to this strain,⁵ which could only infect people who conveniently made extra iron available to it:

Conceivably, hemochromatosis-induced iron overload might have a similar effect, enhancing the virulence of the infecting KIM D27 strain by compensating for its iron-acquisition defects⁶

Patients and pathogens are ecosystems; you need to understand both of them, or you don’t understand either.

1. Even rabies virus, for example, which kills well over 99.999% of the people it infects, has had a half-dozen people survive. Myxomatosis virus let a few rabbits survive, and their progeny became relatively resistant; there are a handful of long-term survivors of HIV treatment; and when we get down to things like ebola and smallpox, 10-30% of infected people survive.
2. Steve Silberman’s twitter account first drew my attention to the report.
3. The quest for iron is a constant struggle for pathogenic (and other) bacteria, and they have evolved all kinds of mechanisms to seize it from the host, while at the same time animals have evolved more and more ways to keep iron away from invading bacteria.
4. Note that this is speculation, not proven!
5. He also had diabetes, which may have made him more susceptible as well
6. Centers for Disease Control and Prevention (CDC) (2011). Fatal Laboratory-Acquired Infection with an Attenuated Yersinia pestis Strain — Chicago, Illinois, 2009. MMWR. Morbidity and mortality weekly report, 60 (7), 201-5 PMID: 21346706

So much of the literature in this area is ultimately circular, I’m pulling out my sparse hair reading through it. By the time we get back to the mid-1990′s, the sequence data are even sparser than my hair by today’s standards — only a few hundred base pairs, or a sampling of restriction sites. But the divergence time estimates have propagated forward from that time to today, recycled through the assumptions of papers in the intervening time. It’s like the genetic equivalent of money laundering!

Conceptually, it’s very reminiscent of the questions about viral mutation rates, although the technical barriers are quite different and (especially for RNA viruses!) the mutation rates are vastly different. For example, Hawks’ post talks about which edge of a two-fold range the human mutation rate falls on — between 2.5 x 10^-8 and 1.1 x 10^-8 mutations per site; in a table I’ve used before we see a ten-thousand-fold range for poliovirus error rate estimates.

RNA virus mutation rates 2

I have to get my kids ready for school now, so I don’t have time to talk about the techniques here — it’s notable that sequencing, though much easier on the tiny viral genomes than on the much vaster human scale, hasn’t completely resolved the issue, though the variation gets smaller as sequencing technology gets getter.

Here are some of my previous posts that mention replication error and mutation rates …

• Influenza variations
• Influenza variations, part II
• DNA virus quasispecies? (Probably not.)
• Norovirus mutation and evolution
• Yellow fever, stasis, and diversification

1. Whose blog you should all be reading
2. CASTRO, C., ARNOLD, J., & CAMERON, C. (2005). Incorporation fidelity of the viral RNA-dependent RNA polymerase: a kinetic, thermodynamic and structural perspective Virus Research, 107 (2), 141-149 DOI: 10.1016/j.virusres.2004.11.004

That light at the end of the sequencing tunnel is a freight train, heading toward us with a mile-long load of data.

Part of the problem is that I’m doing a ton of influenza reading, and I’m reluctant to talk much about influenza here. Maybe that doesn’t make much sense, but I don’t want this to be in any way an “official” blog. I also worry a little about inadvertently talking about unpublished and premature stuff. Still, I’ll probably have some flu stuff here as I get a better grasp on the field.

I usually don’t like to give brief pointer-type posts, but I think that’s what I’m going to try for a little while — short posts pointing to recent papers that have caught my eye, without the background and context I usually try to include, but that I don’t have time (or mental energy) for right now.

Besides catching up on the flu field and preparing to drive down to Atlanta next week to start at the CDC, some other things that are keeping me busy at the moment:

• Finding landing spots for my students. I think we now have found labs and projects for all of them. One will move to the CDC with me and take up a flu project, while remaining an MSU student.  This has all taken a certain amount of paperwork and planning
• Playing catch with my kids in the back yard
• Trying to rearrange my grants. I don’t know if it is possible but I have proposed a new consortium and principal investigator to take over some of them
• Planning the future of my ongoing research projects.  Some will stay at MSU; one will probably move to a group of collaborators
• Arranging a temporary place to stay in Atlanta; looking for a permanent house in the Atlanta area
• Taking my kids to their baseball games (Monday/Wednesday – William; Tuesday/Thursday: Matthew; Friday – makeup games for both). I’m an  ”assistant coach”, which means I tie shoelaces, rig up catcher’s gear, and act as 3rd base coach when I’m not doing the more important shoelace-tying jobs
• Preparing our house here for sale.  Anyone want a lovely home in the East Lansing area? Crayon stains on the carpets will be removed, unless buyer likes the dramatic effect
• Co-ordinating plans with our movers. This is arranged through the government and takes a certain amount of paperwork
• Writing part of a book chapter on influenza
• Working on papers with co-authors. I play a minor role in 3 or 4 papers in press and submitted
• Preparing 3 of my own papers. Two are very close (waiting for replicates on data for the final figures); one could be done but needs to wait for one of the others to be in press before I submit it
• Throwing a goodbye party for our friends here.  Going to goodbye parties thrown by our friends here
• Preliminary exams. I’m on a bunch of students’ thesis committees, and one or two have arranged their qualifying exams to catch me before I go
• Taking my kids to Lansing Lugnuts (our local Single-A baseball team) games
• All the government paperwork involved in starting in the CDC.  There is a lot, and none of it is Mac-compatible, whereas I have no Windows computers available. Hmm.
• Going to our kids’ school for their end-of-year plays, performances, and parties. (Rainforest party this afternoon in Matthew’s class!)

There’s a lot more, but you get the idea.  My kids get off school this Friday, and I plan to spend the next week mostly hanging out with them, so I want to get as much paperwork and so on out of the way this week.

Anyway, I hope I’ll be able to get back into some posts, even if they’re relatively terse, soon.

In handy pretend-question-and-answer format:

What’s the job? My title will be something like “Head of the Influenza Pandemic Preparedness and Vaccine Team“.  Being a government job, it probably sounds rather grander than it is. It’s a small to mid-sized research team  that covers various aspects of influenza pathogenesis, virology, and surveillance, focusing mainly but not only on the non-standard (i.e. non-seasonal) flu strains.

Why are you leaving MSU? I don’t think of it as “leaving MSU”, but rather as “going to the CDC”.  What I mean by that is that I’m very happy at MSU, it’s a great place, my research is going reasonably well, we are very fond of Michigan, and so on.  The only reason I’m changing positions is that I think the CDC position is going to be even more exciting and interesting.  And yes, I’m aware that I’m incredibly fortunate to be able to choose between these two wonderful opportunities.

When are you going? I’m probably moving in mid-June.

Do you have ten thousand and one things to do before then? Yes.

Are you looking forward to summers in Atlanta? No.  I’m Canadian.  I don’t deal well with heat.

What about this blog? There may be some hiccups as I have to worry about moving, selling and buying houses, and learning a bunch of new stuff.  But overall, I think it should keep going.

My main use for an iPad is for the things it’s very good at: My kids watch videos and play games on it, I read books and news and watch baseball games. It’s good for email, great for internet, and you already know all that.

One of the things I had hoped, though, is that I could use it for “real” work: Word processing, spreadsheets, and presentations, using Apple’s iWork apps.  Having taken a look at two of the three: Not so much.

Don’t expect the iPad versions of Pages or Keynote to be very useful.  These are not the full-fledged versions that Jobs sold them as; they’re stripped down mobile versions, missing critical features.  They have a limited number of fonts. (Pages doesn’t have Times New Roman, which is about as basic as you can find. I take it back; Times New Roman is there. But when I imported a document in, I got an error message saying that it didn’t have the font Times New Roman.  No idea why. Symbol is not there, which is a definite problem for people working with alpha-herpesviruses or alpha-beta T cells and so on.) They can’t handle some media types. I don’t know which ones, but a simple presentation I imported into Keynote was riddled with question marks where it couldn’t render images.

(I see that Chris Anderson at The Unofficial Apple Weblog reaches the same conclusion about Keynote.)

The various ways for syncing documents are clumsy and awkward.  I am still hoping that there will be some kind of shared folder eventually that, say, Dropbox can use; but for now you have to drag things back and forth individually.

If you start a document on the iPad, I’m sure it will look fine.  But if you have some documents on your computer, and you’re thinking you’ll be able to use the iPad to work on them down at the coffee shop or on your deck, don’t be too confident.

It’s not a dealbreaker for me, but if you need an iPad for real work, don’t count on this release of iWorks.

Their contributions to my lab plans:

In principle, dying is fine,  because most cells can be easily replaced. ¹ Unexpected cell death isn’t fine, mind you — it means there’s something abnormal going on, and the immune system detects uncoordinated cell death as danger and responds with inflammation — but the usual form of cell death is highly coordinated, with the cell carefully tidying up before blowing out the candles.

This video² helps show just how organized programmed cell death is.  Here we’re seeing a cell whose mitochondria are double-stained.  Cytochrome c is green (it’s part of the mitochondrial energy-generating system); red is a dye that indicates functioning, respiring mitochondria. The cell is forced into programmed cell death.³ At the start the mitochondria are both green and red, making yellow.  Watch the dual waves sweep over the cell: First the cytochrome leaks out, leaving only the red behind, and then — this 15-second movie shows about 10 minutes of activity — the mitochondria wink out altogether as they stop breathing, leaving behind a peaceful corpse.

1. Obviously there are exceptions, like neurons, that aren’t as easily replaced.
2. This is one of the supplementary videos from
   Bhola, P., Mattheyses, A., & Simon, S. (2009). Spatial and Temporal Dynamics of Mitochondrial Membrane Permeability Waves during Apoptosis Biophysical Journal, 97 (8), 2222-2231 DOI: 10.1016/j.bpj.2009.07.056
3. By treatment with TRAIL

Thus, since diverging from the last common mycobacterial ancestor, the leprosy bacillus may have lost more than 2,000 genes. ²

Immunological, because as mycobacteria, leprosy and tuberculosis may have an entire branch of the immune system dedicated to their control and destruction.  Epidemiological, because leprosy is one of the very few diseases that has the potential for elimination without vaccines.  And now let’s add phylogeography and anthropology to the list, with a paper that offers a detailed analysis of leprosy’s migration through humanity. ³

This was done by genetic analysis, tracking through sub-types of leprosy in various areas, both modern and ancient — the latter being “obtained from leprosy graveyards in Croatia, Denmark, Egypt, England, Hungary and Turkey“, and allowing the authors to determine the strains of leprosy that circulated as much as 1500 years ago.  Their conclusions (building on and extending earlier work):

• The progenitor of leprosy arose in East Africa
• New strains then spread into Asia, through two different routes: One northern route, and one southern
• The Southern route into Asia was probably the Silk Road: “the trade route between Europe and Asia known as the Silk Road appears likely to have been a means of transport and disease transmission“.  They point out that this is the opposite path of the Black Plague, which likely spread from Asia to Europe along the Silk Road.
• Another strain of leprosy moved from East Africa westward into the Middle East and Europe
• This strain in turn spawned strains that are found in West Africa and countries linked to West Africa by the slave trade.  (Compare to the phylogeography of hepatitis C, among other diseases spread by slavery)
• Leprosy in North America came from relatively recent European immigrants, rather than coming along with the original Bering Strait peoples.

One interesting conclusion is that the genome decay of M. leprae is much older than humans (occurring over a million years ago, whereas humans are only a few hundred thousand years old), even though the genetic evidence says the present bacteria were clonal just a few thousand years ago.  They suggest that

Alternatively, the genome decay could well be ancient, but M. leprae may only recently have become a human pathogen. For instance, it is conceivable that an ancestral form of M. leprae infected an invertebrate host such as an insect, which later acted as a vector for transmitting the bacillus to humans.  ³

1. Monot, M. (2005). On the Origin of Leprosy Science, 308 (5724), 1040-1042 DOI: 10.1126/science/1109759
2. Cole, S., Eiglmeier, K., Parkhill, J., James, K., Thomson, N., Wheeler, P., Honoré, N., Garnier, T., Churcher, C., Harris, D., Mungall, K., Basham, D., Brown, D., Chillingworth, T., Connor, R., Davies, R., Devlin, K., Duthoy, S., Feltwell, T., Fraser, A., Hamlin, N., Holroyd, S., Hornsby, T., Jagels, K., Lacroix, C., Maclean, J., Moule, S., Murphy, L., Oliver, K., Quail, M., Rajandream, M., Rutherford, K., Rutter, S., Seeger, K., Simon, S., Simmonds, M., Skelton, J., Squares, R., Squares, S., Stevens, K., Taylor, K., Whitehead, S., Woodward, J., & Barrell, B. (2001). Massive gene decay in the leprosy bacillus Nature, 409 (6823), 1007-1011 DOI: 10.1038/35059006
3. Monot, M., Honoré, N., Garnier, T., Zidane, N., Sherafi, D., Paniz-Mondolfi, A., Matsuoka, M., Taylor, G., Donoghue, H., Bouwman, A., Mays, S., Watson, C., Lockwood, D., Khamispour, A., Dowlati, Y., Jianping, S., Rea, T., Vera-Cabrera, L., Stefani, M., Banu, S., Macdonald, M., Sapkota, B., Spencer, J., Thomas, J., Harshman, K., Singh, P., Busso, P., Gattiker, A., Rougemont, J., Brennan, P., & Cole, S. (2009). Comparative genomic and phylogeographic analysis of Mycobacterium leprae Nature Genetics, 41 (12), 1282-1289 DOI: 10.1038/ng.477

… in a household setting, simple, readily available products such as 1% bleach, 10% vinegar and 0.01% washing up liquid all make convenient, easy to handle killing agents for influenza virus A/H1N1. These findings can be readily translated into simple public health advice, even in low resource settings. The public do not need to source more sophisticated cleaning products than these.

–Greatorex, J., Page, R., Curran, M., Digard, P., Enstone, J., Wreghitt, T., Powell, P., Sexton, D., Vivancos, R., & Nguyen-Van-Tam, J. (2010). Effectiveness of Common Household Cleaning Agents in Reducing the Viability of Human Influenza A/H1N1 PLoS ONE, 5 (2) DOI: 10.1371/journal.pone.0008987

(My emphasis) Their figures show that these common solutions almost immediately reduced the numbers of virus from between 1 and 100 million at the start, to undetectable levels (less than 200). Hot water, not surprisingly, didn’t work.

They also added that “branded anti-bacterial wipes and anti-viral tissues were encouragingly effective at inactivating the virus“, so if you’d rather buy something expensive, go ahead.

1. Aiello, A., Murray, G., Perez, V., Coulborn, R., Davis, B., Uddin, M., Shay, D., Waterman, S., & Monto, A. (2010). Mask Use, Hand Hygiene, and Seasonal Influenza?Like Illness among Young Adults: A Randomized Intervention Trial The Journal of Infectious Diseases, 201 (4), 491-498 DOI: 10.1086/650396