Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

May 6th, 2012

The Horse Plague

The Horse Plague
The horse plague — sketches about town during the epidemic, by Theodore R. Davis. From Harper’s weekly : a journal of civilization.  1872

 

On the evening of October 21st only a few animals were affected, but on the morning of the 22d there was scarcely an animal of the equine species that was not affected.  Horses, mules, and even a zebra.  More than twenty thousand were suffering in different degrees. 1

(See also Influenza before 1918, part II: 1872)


  1. Annual report of the Department of Health of the State of New Jersey. By The New Jersey State Dept. of Health, 1877 (“Epizootic influenza”, p. 160)  []
February 27th, 2011

Patients, pathogens, ecosystems

Man contracts Plague - E.M. Ward
“A terrified man realizing he has just contracted the plague, surrounded by a group of people.”
By E.M. Ward, 1848.

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[]
January 12th, 2011

An insult to human understanding

Then, it would seem to have been all but unanimous; and now, one would think, at first sight, that it were almost an insult to human understanding to be obliged to collect statistics to prove that vaccination confers a large exemption from attacks of small pox, and almost absolute security against death from that disease. … The general ignorance of the community, especially of the lower orders, as to the aim and object of vaccination, is lamentably great, and has still to be overcome.

–William Aitken
The Science and Practice of Medicine, Vol. I (Second edition)
Charles Griffin and Company, London, 1863

December 8th, 2010

Do TRegs discriminate?

As I’ve noted several times before, regulatory T cells are important reasons for the poor immune response to tumors. TRegs are normal components of an immune response, “designed” to keep inflammation from running riot in general and to prevent responses to self-antigens in particular. Whether it’s because tumors are mostly (though not solely) self antigens, because tumors are chronic sources of stimulation that could lead to inflammation running riot, or because tumors “learn” how to specifically trigger TReg-like responses, TRegs are common features of tumors.

Eliminating TRegs, in mouse models of cancer, often allows a strong immune response to the tumor. An interesting spin on this was shown in a recent J Immunol paper.1 It seems that the TRegs don’t generally suppress all the response, they shut down the responses to some targets harder than others:

Our results indicate, therefore, that depletion of Tregs uncovers cryptic responses to Ags that are shared among different tumor cell lines. CT26-specific T cell responses can be elicited by different forms of vaccination in the presence of regulatory cells, but in these cases T cell responses are highly focused on a single tumor-specific epitope …Taken together, these data suggest that immune responses to some Ags are more tightly regulated than others.  1

In other words, even though you might be able to force a protective immune response to a tumor by vaccinating in the presence of TRegs, when you get rid of TRegs the response is broader, and targets T cell epitopes that otherwise wouldn’t look like they’re epitopes at all.

I wonder if this goes on with “normal” (say, viral or other non-tumor) epitopes – whether this sort of thing might help explain some forms of immunodominance. I kind of doubt it, but the phenomenon does sounds a little like revealing a subdominant response.

I wonder also how this ties in with a recent paper that suggested TRegs in tumors are highly focused on a small subset of tumor epitopes. Could they be more broadly-based, but on epitopes that are otherwise invisible? Again, I kind of doubt it, but it’s an intriguing idea.  Maybe the universe of tumor epitopes available for attack is much larger than we realize.


  1. James, E., Yeh, A., King, C., Korangy, F., Bailey, I., Boulanger, D., Van den Eynde, B., Murray, N., & Elliott, T. (2010). Differential Suppression of Tumor-Specific CD8+ T Cells by Regulatory T Cells The Journal of Immunology, 185 (9), 5048-5055 DOI: 10.4049/jimmunol.1000134[][]
December 4th, 2010

“Lots of flim-flam, but very little reliable information”

NASA’s shameful analysis of the alleged bacteria in the Mars meteorite made me very suspicious of their microbiology, an attitude that’s only strengthened by my reading of this paper.

Rosie Redfield reviews the NASA arsenic-in-bacteria paper.

Read it.

November 30th, 2010

HIV evolution: individual vs. population

Worldwide HIV/AIDs Epidemic Statistics
Worldwide HIV/AIDs Epidemic Statistics

(We are in the process of selling one home and buying another, while at work I just finished organizing a course on biosecurity for an international group. In the upcoming week I’m traveling to a conference in Washington. To say nothing of the Thanksgiving holiday. All this means short and scarce updates for a little while.)

We know that the immune response to HIV forces the virus to evolve at great speeds, so that the viral targets of the immune response change and become at least temporarily invisible. We also know that the specific targets are different for almost every infected person. So although you have rapid evolution in each individual, what does this mean to overall evolution of the global population of HIV?

The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.1

(My emphasis) This is a modeling study (though it did look at real-life data to some extent), but their conclusion is consistent with larger-scale population studies as well; see my previous post here and links therein.


  1. Fryer, H., Frater, J., Duda, A., Roberts, M., , ., Phillips, R., & McLean, A. (2010). Modelling the Evolution and Spread of HIV Immune Escape Mutants PLoS Pathogens, 6 (11) DOI: 10.1371/journal.ppat.1001196[]
November 10th, 2010

Rinderpeste through the years

Rinderpeste (1880)

RINDERPEST. Lips and gums, showing apthous condition1

1711 (via 1902):

Rinderpest is the most fatal disease affecting cattle. … The first great epizootic of which there seems to be records occurred about 1709 and spread over nearly all of the countries of Europe. It is reported that 1,500,000 cattle died from its effects during the years from 1711 to 1714. 2

1839 (via 1861):

Previously to the present century the only well recognized epizootics that are known to have prevailed extensively among horned cattle in Europe were the Eczema Epizootica, or “mouth and foot disease”, a complaint well known in England since the year 1839, and the terrible Rinderpest or Steppe murrain.

This last named disease, which is described as being of the nature of a highly infections typhus fever, terminating in dysentary, is said to be indigenous to the Steppes of Tartary and Siberia, from whence it has descended, from time to time, upon Russia, Germany, and other European countries.

It has been estimated that during the eighteenth century the Rinderpest destroyed, in Europe, as many as two hundred millions of cattle.3

1865 (via 1880) :

In 1865 the plague appeared in Holland, and was carried thence to England. In both countries the disease carried off one hundred thousand head of cattle in the course of a few months.4

1889 (via 1909):

About the year 1889, or shortly before, a virulent form of rinderpest started among the domestic cattle and wild buffalo almost at the northern border of the buffalo’s range, and within the next few years worked gradually southward to beyond the Zambesi. It wrought dreadful havoc among the cattle and in consequence decimated by starvation many of the cattle-owning tribes; it killed many of the large bovine antelopes, and it wellnigh exterminated the buffalo.5

2010:

14 October 2010, Rome – An ambitious global effort that has brought rinderpest, a deadly cattle plague, to the brink of extinction is ending all field activities, paving the way for official eradication of the disease.6


  1. Contagious Diseases of Domestic Animals. Department of Agriculture. Washington. Government Printing Office. 1880[]
  2. The Pathology and Differential Diagnosis of Contagious Diseases of Animals. Veranus Alva Moore. Taylor and Carpenter. Ithaca, N.Y. 1902[]
  3. REPORT of the COMMISSIONER OF PATENTS for the year 1860: AGRICULTURE.
    Washington. Government Printing Office. 1861[]
  4. Cattle Plague or Rinderpeste. A history of the Disease. in: Report of the C0mmissioner of Agriculture for the year 1879. Washington. Government Printing Office. 1880[]
  5. African Game Trails. Theodore Roosevelt. Charles Scribners’ Sons. 1909[]
  6. FAO Media Office[]
November 4th, 2010

Mutation rates in man and virus

John Hawks1 has a long and very interesting post on the human mutation rate — not just the actual number (which turns out to be less well documented and much more slippery than I had realized), but the techniques used to calculate the rate, and difficulties therein.

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.

Virus polymerase error rates
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 …


  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[]
November 3rd, 2010

Shield or target? A downside of immune evasion

T cells & herpes simplex
T cells (green) and herpesvirus-infected cells (red)
(from Akiko Iwasaki)

We know that lots of viruses, especially herpesviruses, block antigen presentation. The assumption has been that they are thereby preventing T cells from recognizing infected cells, though long-term readers of this blog1 will know that I’ve been puzzled about the details of this for quite a while.

A recent paper2 raises yet another complication for this pathway: In humans3 there are T cells that specifically recognize cells in which antigen presentation is blocked:

Our data indicate that the human CD8+ T cell pool comprises a diverse reactivity to target cells with impairments in the intracellular processing pathway2

If so, you might wonder why the viruses would bother blocking antigen presentation. They might avoid recognition by T cells specific for the viral proteins, but at the cost of being recognized and eliminated by the T cells that recognize antigen-presentation-defective cells.

As always, I don’t have an answer. I do have the unhelpful observation that viruses are incredibly subtle and efficient, and given that herpesviruses have apparently maintained the ability to block antigen presentation for some 400 million years it’s presumably useful to them. I’ll also add the even more unhelpful observation that immune systems are also incredibly subtle and efficient and have also persisted for 450 million years.

How Not to be Seen

However, there may be a clue in the techniques that Lampen et al used to turn up this subset of T cells: They used multiple rounds of stimulation, which is going to expand these cells massively. We don’t know how abundant they are inside a normal human – perhaps they are so rare that they don’t have a chance to impinge on herpesvirus infection early enough.

The catch with that, though, is that tumors also frequently get rid of antigen presentation via mutation; in fact, eliminating antigen presentation seems to be one of the most common forms of mutations in cancers, suggesting that it’s an important part of their ability to survive and expand in the face of immune attack. Tumors are immunologically present much longer than viruses ((Although herpesviruses set up a lifelong infection, most of that is generally in a non-immunogenic, latent form). So why doesn’t this long-term tumor presence lead to amplification of these antigen-presentation-deficient-specific T cells that would eliminate the tumor?

My guess here is that this is where TRegs come in. As I said in a recent post, TRegs are very commonly, if not universally, associated with tumors, and prevent immune attack on the tumor. I wonder if the tumors mutate to avoid T cell recognition early in their development, before they are able to trigger the TReg response; that allows them to grow large enough and long enough that by the time the presentation-defect-destroyers kick in, the tumors have their TReg defenders set up.  (I admit that this doesn’t account for the correlation between a tumor’s loss of antigen presentation, and poor prognosis, but I leave this as an exercise for the reader.)

And, of course, where either of these defense systems for the proto-tumor fails, we normally would simply not see any tumor at all. Perhaps this is happening all the time inside us — proto-tumors are being eliminated by T cells, some are mutating their antigen presentation pathway and lasting a little longer and are then eliminated by a different subset of T cells, and we never know it.


  1. If any[]
  2. Lampen, M., Verweij, M., Querido, B., van der Burg, S., Wiertz, E., & van Hall, T. (2010). CD8+ T Cell Responses against TAP-Inhibited Cells Are Readily Detected in the Human Population The Journal of Immunology DOI: 10.4049/jimmunol.1001774[][]
  3. As has been previously shown in mice[]
October 28th, 2010

Immunological standoff

TRegs infiltrate a tumor
TRegs infiltrate into a tumor

There’s increasing evidence supporting the notion that tumors are often not rejected by the immune system because regulatory T cells actively block the immune response to the tumor cells. 1

That means that within the tumor, two branches of the immune response are fighting it out. If the TRegs win, the tumor will not be rejected (and may eventually kill the host); if the rejection branch2 wins, the tumor may be rejected and the host may survive a little longer.

Both TRegs and rejection-branch T cells are driven by specific antigen. That is, as opposed to the general patterns that drive innate immune responses, the T cells are activated by peptides associated with major histocompatibility complexes (mainly class II MHC, for the TRegs).

So that raises an interesting question: What specific peptides activate the TRegs in the tumors, and are they different from the ones that activate rejection-type CD4s?

The question is even more interesting than it may seem at first glance, because3 there are different TReg subsets with different peptide preferences. One set of TRegs likes to see ordinary self-peptides: Peptides that are naturally present, and that should not be rejected because, well, they’re part of you. “Normal” rejection-type T cells don’t see those peptides, because those that do are killed during their development (or are converted into TRegs during development, probably). The other group of TRegs sees foreign peptides, that would be expected to be rejected. You need these TRegs as well, because there are times when a chronic immune response, even to a foreign invader, is more harmful than the invader itself; so under those circumstances, some rejection-type T cells get converted into TRegs, and those can shut down the response to the invader, hopefully to reach a happy accommodation.

Are the TRegs in tumors the first kind, that are activated by the normal self-antigens that are present in the tumor cells (which are, remember, originally you to start with)? Or are they the second type, responding to the foreign antigen present in the tumor (mutated proteins, say, or over-expressed growth factors) but converted into a TReg type from a rejection-type when the tumor foreign antigens proved to be a chronic stuimulus?

Reservoir Dogs StandoffA recent paper4 suggests it’s the latter:

This allows us to ask whether tumor-associated Treg cells arise from the repertoire of TCRs used by natural Treg cells or from the repertoire used by effector cells. We show that Treg population in tumors is dominated by T cells expressing the same TCRs as effector T cells. These data suggest that Treg in tumors are generated by expansion of a minor subset of Treg cells that shares TCRs with effector T cells or by conversion of effector CD4+ T cells and thus could represent adaptive Treg cells. 4

If this is generally true (and the authors do offer a helpful series of caveats) it has a very important implication. There’s a huge amount of interest in tumor vaccines — identify an antigen specific for the tumor, and induce a potent immune response to it, in the hope that T cells will then reject the tumor. But you see the problem: If the TRegs are stimulated by the same antigen, then your vaccine is going to increase both sides — the rejection branch and the TReg branch — and you’re no further ahead than when you started! This may be one of the reasons that tumor vaccines have been only intermittently effective. But it does make even more attractive another approach toward cancer immunization, where TRegs are specifically blocked, hopefully allowing the already-present rejection-type5 T cells to kick in and, maybe, eliminate the tumor:

This further suggests that improved cancer immunotherapy may depend on the ability to block tumor-antigen induced expansion of a minor Treg subset or generation of adaptive Treg cells, rather than solely on increasing the immunogenicity of vaccines. 4


  1. I’m not quite comfortable with the phrasing here, but I can’t come up with a non-lawyerly, succinct way to phrase it. TRegs are part of the immune system, and so when they’re active the immune system isn’t blocked, it’s highly functional. What’s being blocked is what we traditionally think of as an immune response — the aggressive response that causes inflammation and that kills targets — while the TReg form is the branch of the immune response that prevents all those things. When TRegs are dominant, the immune response isn’t easily visible, but it’s still an active immune response.[]
  2. Again, not happy with the term; if anyone has a more felicitious phrase, let me know[]
  3. My qualifier here is “For now”, because this is a rapidly-changing field that has kind of outstripped my ability to follow it right now; I’m not quite sure whether this is the consensus view any more[]
  4. Kuczma, M., Kopij, M., Pawlikowska, I., Wang, C., Rempala, G., & Kraj, P. (2010). Intratumoral Convergence of the TCR Repertoires of Effector and Foxp3+ CD4+ T cells PLoS ONE, 5 (10) DOI: 10.1371/journal.pone.0013623[][][]
  5. Having typed that a dozen times here, I like it less than ever[]