Mystery Rays from Outer Space

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

August 26th, 2010

“How quickly we forget the ravages of disease”

City Health Detroit 1920
In 1920 there was an outbreak of smallpox in Detroit (see the map below). Of the 133 cases with known history, only two had been vaccinated in the previous 10 years — three others had been vaccinated 12, 60, and 80 (!) years previously; the remainder were unvaccinated. The Detroit Department of Health had this commentary (my emphasis):

Using Knowledge

How quickly we forget the ravages of disease! In the autumn of 1918 the world was visited by the worst plague of recent times — influenza. Probably 1 per cent of the population of the globe was swept away by this scourge. People raved and bewailed at their helplessness. There was no known preventative. We know that crowding aided this disease, but as a reliable preventive against influenza, telling a person to avoid crowds in a congested city has about as much effect as telling a fly to keep out of baby’s cup of milk.

In 1920 influenza returned and exacted further toll of lives. The previous epidemic had not produced an antidote nor a preventative of influenza. The bacteriologists have not been idle. They have worked industriously trying to discover the true cause of the disease and a means of immunizing against it. It is not to their discredit that their efforts have not met with success.

Smallpox is another matter. Jenner, an English physician, proved beyond a shadow of a doubt that material from a pox pustule in a cow when added to the scarified skin of human beings gave them immunity against smallpox. This was in 1796. Vaccination soon became universal.

Boston’s experience is interesting. In 1721 out of a population of 11,000 there were 5,989 cases of smallpox and 850 deaths. In 1730 in a population of 15,000 there were 4,000 cases and 509 deaths. After vaccination had been introduced the disease practically disappeared. From 1811 to 1830 there were but 14 cases. Smallpox has disappeared where compulsory vaccination is in effect.

We do not know how to immunize against influenza.

We do know how to immunize against smallpox.

Shall we utilize this knowledge or not? If not why continue to search for an influenza panacea? If it is not to be used, once discovered, why waste time and effort to discover it? 1

See also earlier posts:

Smallpox in Detroit - map, 1920


  1. City Health. Monthly Bulletin, Detroit Department of Health.  May 1920. Vol. III, No. 8[]
August 24th, 2010

Adenoviruses and the occupied sign

Adenovirus
“Adenovirus” (by Mapposity)

There are two aspects about virology that constantly amaze me: How much we know about viruses, and how little we know about viruses.

Adenovirus research offers examples of both. Adenoviruses are probably among the best-studied virus groups.1 We really do know an amazing amount about them. But it was only last year that Linda Gooding’s group offered the most convincing demonstration yet that adenoviruses actually establish a truly latent infection — a really basic aspect of their lifestyle, 2 and a new paper from her group3 is looking at some equally-basic implications of that finding. (I talked about Gooding’s earlier latency finding here.)

It’s been known pretty much since day 1 that adenoviruses persistently infect tonsils;4 that was why they were first isolated, when the virus grew out of apparently-normal tonsil tissue in culture. The critical distinction is between mere “persistence” and true “latency”. In a latent infection, the virus shuts down production of new viruses, and is maintained basically as DNA within the host cell. Persistence is cruder — the virus continues to replicate, but at a low level that balances its destruction. Simplistically, latency is a destruction-free process, while persistence can include viral and cellular destruction.

Adenoviruses establish their latency in tonsils, which of course have lots of lymphocytes, but we usually think of adenoviruses as infecting epithelial-type cells, or hepatocytes, or whatever. Clinically, these guys typically cause cold-type symptoms, which you tend to get from fairly superficial infections of the respiratory tract lining. We don’t tend to think of adenoviruses as effective infectors of lymphocytes, but it turned out that their latent infection was, in fact, in T lymphocytes.  It looks like adenoviruses have one cell type (epithelial-type cells) for a lytic infection that leads to shedding of infectious virus, and another cell type for latent infection, allowing the virus to remain in the host and potentially re-infect an epithelial type later on.

Accordingly, Gooding and her team set up infections of cultured T lymphocytes in vitro, to see what would happen. In particular, they wanted to know whether, and how, the viral replication cycle would be controlled; and whether and how the host cell would be affected by the infection. I will skip over most of their findings and and highlight a couple that surprised me:

Occupied!(1) The “Occupied!” sign. To get into a cell, adenoviruses usually need to bind to their cellular receptor, the CAR receptor.5 But latently-infected cells almost permanently shut off this receptor. For hundreds of days after the initial infection, cells express little or no CAR. The latent virus doesn’t want any competition; it has found a congenial long-term environment, and it doesn’t want some interloper infecting its cozy cell and perhaps destroying it.

There seem to be several mechanisms for the shutdown, but at least part of it is that the virus apparently permanently modifies the host DNA:

CAR synthesis and expression remained repressed even after the viral genome was lost (Fig. 8 and data not shown), suggesting a virus-induced epigenetic change to the cells that does not require the continued presence of the virus.3

And in fact the CAR isn’t the only thing to be modified for this purpose:

Even when CAR levels were restored by transduction with a CAR-containing retrovirus, the previously infected cells could not be reinfected3

We don’t know how the latent viruses were blocking superinfection, but it’s clear that the latent viruses really don’t want company.

(2) Rearranging the furniture.  The latent virus doesn’t stop at hanging an “occupied” sign; it modifies its host cell in other ways as well, apparently again by long-term or even permanent epigenetic modification of the DNA. That means that even after the virus itself is altogether gone, not even latently present, there are modified cells hanging about:

Remembering that adenoviruses infect just about everyone, that may mean that we’re all walking around carrying cells that are tagged and functionally altered by these viruses.

There’s been speculation for many years that adenovirus infection may underlie some forms of human tumors. One argument against this has been that there’s no evidence of adenovirus DNA in tumors, for the most part.6 (One rule of thumb in determining if a virus is actually causing a tumor is if it’s actually present in the tumor.) But of course, if adenoviruses leave a permanent scar on cellular DNA that lasts longer than the virus itself, this may not be relevant:

One compelling reason to gain an understanding of this nonlytic infection is the likelihood that adenovirus gene products cause damage to the host cell genome. … While these functions are irrelevant to the lytic infection of epithelial cells where all infected cells die, they are of serious concern when infected lymphocytes have carried the viral genome and survived. … Despite this normal appearance, the cells display altered gene expression long after the virus is lost.3


  1. There are over 40,000 papers on adenoviruses, or at least mentioning them, in PubMed.[]
  2. To be fair, it’s been suspected for decades that they do go latent, but that was the first time it was actually proven.[]
  3. Zhang, Y., Huang, W., Ornelles, D., & Gooding, L. (2010). Modeling Adenovirus Latency in Human Lymphocyte Cell Lines Journal of Virology, 84 (17), 8799-8810 DOI: 10.1128/JVI.00562-10[][][][]
  4. I’m going to limit this discussion to the Group C adenoviruses — the latency concept may be true for other groups of adenoviruses but that hasn’t been directly shown.[]
  5. “CAR” stands for the “Coxsackie B virus and Adenovirus Receptor”. Can anyone guess what other virus uses this receptor? Bueller? Anyone?[]
  6. Also, the epidemiological links between tumors and adenoviruses are not very strong, at least in humans.[]
August 19th, 2010

And so on, ad infinitum

Rosy Apple Aphid (Whalon lab)
Rosy Apple Aphid (Whalon lab, MSU)

Normally I don’t talk about research that’s well covered elsewhere, but I like this one so much (and it links back to so many of my earlier posts; check the footnotes for those links) that I’ll make an exception here.  I’d seen bits and pieces of this story, but I didn’t have the big picture until I listened to Carl Zimmer’s1 latest Meet The Scientist podcast2 where he interviewed Nancy Moran.3

So this is kind of about insect immunity. Insects have lots of innate immune responses, the short-term sorts of things that in vertebrates we call ‘inflammation’, but they don’t have the long-term adaptive responses 4 that incorporate antibodies and T cells — those systems arose in sharks and their progeny (and, apparently mostly independently, in lampreys and hagfish,5 but that’s a different story).

The hallmark of adaptive immunity, in contrast to innate immunity, is its flexibility: Different responses for different agents, and capable of changing as the target changes.  So insects can’t do that, although of course their immune system has worked pretty well for a few hundred million years.

Except aphids have a sort of changable immune response.  How does that work?

Parasitic wasp of aphids
Parasitic wasp laying eggs in an aphid
(from
University of Wisconsin)

This is an immune response, not to bacteria or viruses, but to parasitic wasps.  Aphids are popular targets for some of these wasps: The wasps lay eggs in the aphid, the eggs hatch into baby wasps, and the baby wasps eat the aphids from the inside out until they kill the aphid and then they fly away to predate some more.  Except in some aphids, the baby wasps are killed as they hatch, and the aphids survives to make more aphids.

And this immunity to the wasps is — on a population basis, not an individual basis — rather flexible. Insects in general are good at evolving toxin resistance over years or decades, but aphids have apparently been doing this over millions of years. It turns out that different aphids kill the baby wasps in different ways, using different toxins to do so, and the toxins change over time as well.  So the wasps can’t develop resistance to the toxins.  It’s a little bit — a very little bit — like an adaptive immune system, at least in broad terms.

Not all aphids are immune at all (or there would be no wasps).  You can take susceptible aphids and make them resistant, though. You just have to infect them with a particular bacterium.  This is a symbiotic6 bacterium, that only lives in aphids — it’s dependent on the aphid host to provide it with essential nutrients — and these bacteria carry toxin genes. They help their host survive by providing toxin genes, that kill the wasps that parasitize the hosts the bacteria are symbiotic with.

But not so fast! The bacteria don’t naturally have toxins! The toxins come from parasites of the bacteria! There are bacteriophages, viruses that infect the bacteria, that carry the toxins.  When the viruses parasitize the bacteria that are parasitizing the aphids, then the parasitic wasps can’t parasitize the aphids that are hosting the bacteria that are hosting the viruses!

And if you look at the bacteriophages as a population, they have a section of their genome that is highly diverse. That part is the region that carries the toxin. Different phages, different toxins, that can spread to new bacteria and then to new aphids, so the aphids can have a supply of new toxins to take care of newly-resistant wasps.

Just to make this even more complex, you know how the wasps subdue their prey? They inject in a complex mix of toxins that shut down the insect immune system. Guess where those toxins come from?7 From the symbiotic viruses8  that the wasps have incorporated into their own genomes millions of years ago, that carry immune evasion genes that the wasps have adapted to use to subdue the aphids that carry the bacteria that carry the viruses that provide the toxins that protect the aphids against the wasps that carry their own viruses to attack the aphids.


  1. Ed Yong also covered this story last year.[]
  2. By the way, you all should be listening to Meet the Scientist.  Zimmer is not only an excellent writer, he does a really good interview, and the scientists he interviews are all highly articulate and interesting.  Scientists as a group tend to be pretty articulate about their work, because communication is actually part of the job description, but Zimmer is very good about asking the right questions and then getting out of the way.[]
  3. A few of the papers by Moran and her colleagues:
    • Oliver KM, Degnan PH, Hunter MS, & Moran NA (2009). Bacteriophages encode factors required for protection in a symbiotic mutualism. Science (New York, N.Y.), 325 (5943), 992-4 PMID: 19696350
    • Degnan PH, Yu Y, Sisneros N, Wing RA, & Moran NA (2009). Hamiltonella defensa, genome evolution of protective bacterial endosymbiont from pathogenic ancestors. Proceedings of the National Academy of Sciences of the United States of America, 106 (22), 9063-8 PMID: 19451630
    • Degnan PH, & Moran NA (2008). Evolutionary genetics of a defensive facultative symbiont of insects: exchange of toxin-encoding bacteriophage. Molecular ecology, 17 (3), 916-29 PMID: 18179430
    • Degnan PH, & Moran NA (2008). Diverse phage-encoded toxins in a protective insect endosymbiont. Applied and environmental microbiology, 74 (21), 6782-91 PMID: 18791000[]
  4. Earlier posts on insect immunity:
    Invertebrate memory, or wishful thinking?
    “Social immunity” in ants?
    “Social immunity” followup []
  5. Posts on lamprey and hagfish immunity:
    Same trip, different routes: Lamprey immunity
    Lampreys got antibodies
    Lamprey VLR and antigen binding
    Lamprey immunity, again[]
  6. Posts on other arthropods and their symbiotic viruses and bacteria:
    How the aphid got its wings
    More symbionts and flight []
  7. To be honest, I didn’t check the kinds of wasp here, so I don’t know for sure that these are among the families of wasps that do this[]
  8. Posts on wasps and their symbiotic viruses:
    Bioweaponized wasps
    Not merely bioweaponized, but mutualistic bioweaponized wasps[]
August 17th, 2010

Pigs (and their viruses) fly

Type II PRRSV An emerging disease that I just missed directly seeing emerge is PRRS.

PRRS is “porcine reproductive and respiratory syndrome”, which pretty much sums up the disease. It’s caused by — you’ll never guess — Porcine reproductive and respiratory syndrome virus (PRRSV), an arterivirus that emerged in 1987. That was the year I left large animal veterinary practice, so I never had a chance to deal with PRRS clinically.

Twenty-three years may not seem like all that long a time, but if you’re an RNA virus that’s a lot of generation times and a whole lot of time for mutations and evolution, and PRRS viruses are an evolutionarily mess. 1 There are North American type PRRSV viruses and European type viruses, there are mysterious clusters of related viruses, there are clusters of related diseases, there are thousands of sequences, and it’s just kind of baffling what’s gone on with the whole schtick.

A new paper2 has tried to sort out part of the mess by analyzing some 8624 North American-type PRRSV sequences, from nearly a dozen countries, and working out evolutionary relationships between them all. 3 (The focus on the North American series — the Type II PRRSV — is because this group seems to be a more common source of disease; although the European strains are far from rare themselves.)

There were a couple of interesting points that parallel some other viruses:

1. Feral vaccines. It’s already known, or at least strongly suspected, that some of the modified-live PRRSV vaccines have started to go feral on a small scale (not nearly as dramatically as the vaccinia virus I mentioned a while ago), and that’s supported by this genetic analysis:

In the vaccine-associated sublineage phylogenies (data not shown), there were a number of well-supported small clusters that might reflect the small-scale transmission of the vaccine viruses in the field … 2

As well as vaccinia, there are other live vaccines that are known to spread into the population. The sort of limited transmission that seems to be showing up here is more typical of this sort of thing than are the vaccinia instances I talked about before.

2. The amazing flying pigs. Even though this is just one of the two major sub-groups of PRRSV and it’s less than 25 years since it emerged, they came up with nine fairly distinct lineages of the virus (see the figure to the right). As you’d expect the lineages speak to the history of the virus — which is to a large extent the history of the pigs that carried the virus.4

This version of the virus probably started out in North America (though how it got there … ?) and then got introduced into other countries on several independent occasions. Two of these introductions were in the late 1980s, shortly after the North American emergence. Aside from that there’s evidence of a bunch of smaller introductions:

… lineage 1 had several Thai sequences clustered with early Canadian sequences … ; lineage 8 contained highly pathogenic Chinese strains and their relatives … ; and lineages 8 and 9 had several Italian isolates which were distributed separately along the phylogeny …, indicating independent introductions of PRRSV from the United States to Italy. 2

They were even able to identify smaller-scale travel patterns, between individual states in the USA:

Iowa plays a central role because its viruses were introduced recurrently to all nine other states (Fig. 5B). The remaining states were not just receiving sites. Their local strains also were transmitted to other states repeatedly, but within a narrower range. … Our phylogeographic analyses reveal, for the first time, an interstate PRRSV traffic network in the United States. … The result also indicates that long-distance spread is a frequent process for PRRSV … 2

This is a reminiscent of the history of the pandemic H1N1 influenza virus, when it was still in swine. (Remember that pandemic H1N1 is genetically  a mixture of a North American swine influenza strain and a Eurasian strain.)  There’s a large national and global traffic in pigs, and even though most countries are reasonably careful in the way they handle incoming pigs it’s not a guarantee against virus introduction. I’m not singling out pigs, either — other kinds of livestock also are global travellers, and obviously so are humans.  But it’s a reminder that it isn’t just humans and their viruses that can quickly travel and spread around the globe.


  1. More correctly, our understanding of their evolution is a mess. The viruses are doing just fine.[]
  2. Shi, M., Lam, T., Hon, C., Murtaugh, M., Davies, P., Hui, R., Li, J., Wong, L., Yip, C., Jiang, J., & Leung, F. (2010). Phylogeny-Based Evolutionary, Demographical, and Geographical Dissection of North American Type 2 Porcine Reproductive and Respiratory Syndrome Viruses Journal of Virology, 84 (17), 8700-8711 DOI: 10.1128/JVI.02551-09[][][][]
  3. That’s a lot of viruses, but the sampling is heavily biased to a limited number of places, especially the USA [and especially a few regions within the USA] so it’s probably an underestimate, and maybe a severe underestimate, of the global diversity.

    I didn’t know, by the way, that there’s a PRRSV Database:http://prrsvdb.org/[]

  4. Or of the pig’s fluids. I think that especially in the early days of the emergence, the virus was spread by the boar semen used for artificial insemination.[]
August 10th, 2010

DNA virus quasispecies? (Probably not.)

I’ve talked about quasispecies several times, and emphasized that RNA viruses, with their high replication error rates, are most prone to forming quasispecies.

I’ve also pointed out, though, that actually measuring quasispecies is technically difficult, and measuring it for the larger DNA viruses would be even harder. You’d need to run sequences on many viral genomes, to see how much variation develops over time; and it’s only recently that sequencing tech has approached the point where it’s even thinkable, let alone affordable, to do that:

While large DNA viruses are thought to have low mutation rates, only a small fraction of their genomes have been analyzed at the single-nucleotide level.1

So maybe DNA viruses might actually form quasispecies, and we don’t know it?

In fact, even for DNA viruses, mutants appear fairly quickly, given the appropriate selection pressure. In principle, these might not even be new mutations, but simply expansion of a particular part of a quasispecies that was already pre-existing. (It’s probably a fairly obvious point, but it’s important to remember that the introduction of new mutants, and their selection and expansion, are completely different processes. Some viruses throw out incredible numbers of mutants, but almost all of them are dead ends that are actively selected against, or at the least not selected for. Other viruses may make far fewer mutants, but given strong enough selection pressure some of these might rapidly take over the population. It’s very tricky to use observed mutations as a measure of mutation frequency, because observation often depends on selection to build up the numbers of the mutant before you can see it.)

At any rate, it’s a fair enough question,2 but recently there has been some evidence that supports the concept of DNA virus genome stability. Wayne Yokoyama’s lab has actually sequenced multiple genomes of mouse cytomegalovirus (a large DNA virus — a member of the herpesvirus family) to look at quasispecies.1

One of the things they did find was a significant number of variations in their stock, compared to the stock they had got it from years before:

… our laboratory’s Smith strain MCMV differed from the previously published Smith strain … There were 452 differences, including 50 insertion/deletions (indels) and 402 single-bp substitutions. … this high number of differences suggested that MCMV mutated in vivo, as we had previously maintained our MCMV stock by in vivo passages. 1

In other words, the standard methods of maintaining a virus — repeatedly growing new stocks in cells, and using those new stocks to make yet more — allow the accumulation of variations in the genome — which is already well known, of course, but often neglected in lab experiments.  Again, as I point out above, the number of observed mutations we see here doesn’t tell us much about the actual mutation frequency.

How often do mutations arise? By running the virus through cells repeatedly (in vitro, that is) and then seeing how individual clones differed, they determined that there are very, very few mutations per replication. What’s more, and even more impressively, very few mutations appeared after passages through mice (in vivo):

… the remaining 9 mutations allowed us to estimate the mutation rate of MCMV as 1.0 x 10–7 mutations per bp per day after in vivo passage, very similar to the mutation rate calculated for in vitro passage.1

(My emphasis) For comparison, the MCMV genome is not quite 250,000 bp long, so we’re looking at around one mutation per 40-50 genomes per day (if I’m dividing right). That’s hundreds of times more stable than most RNA viruses (see the table here3 for some RNA virus error rates).  Still, there’s plenty of room for natural selection in there, because of course there are hundreds or thousands of new MCMV genomes being made per day even in the most conservative estimate (and maybe more like millions or hundreds of millions), so dozens to thousands of them are mutants.

So, not surprisingly, Yokoyama’s group was able to detect a cluster of mutations that were almost certainly selected in the mouse; without going into detail, these mutations were in a viral gene (m157) that’s known to be recognized by the (laboratory) mouse immune system, so it wasn’t surprising that mutants were selected. And such mutants did not appear in mice without the appropriate immune component, demonstrating the role of natural selection in this cluster.

They offer a number of cautions, including one that’s raised in almost all such studies:

One caveat to our mutation analysis is that lethal mutations were probably underrepresented in the final DNA pool since, by definition, they did not propagate. Nonetheless, this limitation is intrinsic to all mutation analysis.1

Still, the results are solid and reassuring, supporting a basic concept in viral evolution.


  1. Cheng, T., Valentine, M., Gao, J., Pingel, J., & Yokoyama, W. (2009). Stability of Murine Cytomegalovirus Genome after In Vitro and In Vivo Passage Journal of Virology, 84 (5), 2623-2628 DOI: 10.1128/JVI.02142-09[][][][][]
  2. Well asked, invisible non-existent person![]
  3. 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[]
August 5th, 2010

The good old days, revisited

As a general remark, the Measles were mild, while on the contrary, the Mumps were almost invariably severe, and frequently attended with metastasis to the testicles. Some cases of the latter were attended with enormous swelling and high inflammatory excitement, requiring the lancet and other antiphlogistic remedies. … As a local application to the scrotum none appeared to afford so much relief, as wheat bran wet with a solution of acetate of lead in vinegar – or with vinegar alone — applied by means of a bandage around the hips, in such a manner as to support the testicle – as its own weight, without such support, was of itself tormenting.

Mumps
“Bad symptoms – a quick pulse – a difficulty in purring – a hoarse mew – decidedly mumps. Recipe some mouse tail soup”

–III. Measles and Mumps in Combination
Western Journal of the Medical & Physical Sciences, Vol. 7 (1834)
Printed and Published Quarterly, at the Chronicle Office, by E. Deming
Cincinnati, Ohio

During the past winter at Camp Lee we have been afforded a rare opportunity of studying mumps in adults. Nine cases of cerebral complications in frank cases of mumps have been encountered and have been made the subject of a special report by Lieut. R.L. Haden, who has had the supervision of the Contagious Disease Service.

These cases were characterized by the occurrence, during an attack of mumps, of increased temperature, headache, vomiting, and frequently evidence of cerebral disturbance, as stupor, delirium, etc.

–MENINGOENCEPHALITIS AS THE ONLY MANIFESTATION OF MUMPS. REPORT OF THREE CASES
By Tasker Howard
The American Journal of the Medical Sciences, Vol. CLVIII, pp. 685-689 (1919)
Lea and Ferbiger, Philadelphia and New York

As a military problem, mumps frequently occurs in men between 21 and 31 years. In the soldier and sailor the infection is dreaded because it is disabling and unmanageable. In 1918 there were 5,756 cases of mumps among 18,000 men at Camp Wheeler, an incidence of 32 per cent. … Orchitis is a frequent and painful complication and when both testicles are involved may cause sterility. Other complications are: great prostration; a tendency to develop mania, or wild delirium, or a comatose state resembling uremia; meningism, mastitis, otitis media, tonsillitis, and pneumonia also occur.

Preventive Medicine and Hygiene, 4th Edition
Milton J. Roseneau
D. Appleton & Company, New York & London, 1921

In an article in this issue of the Journal, Kutty et al [8] assist us in our understanding of the true levels of immunity against mumps in the United States. … As the study demonstrated, the calculated seroprevalence of antibodies to mumps virus in 6–49-year-old Americans is only ~90%, which is below the estimated 92% needed for mumps control (ie, herd immunity).

Quinlisk, M. (2010). Mumps Control Today. The Journal of Infectious Diseases DOI: 10.1086/655395

August 3rd, 2010

Lamprey immunity, again

The Lamprey (Yarrell 1835)
From A History of British Fish (William Yarrell, 1835)

I’ve talked about lamprey immune systems several times (here, here, and here). I find them fascinating because it shows both how our own immune system developed, and also shows alternate routes that can lead to a pretty good, but very different, immune system.

Quick background: In order of evolutionary appearance you have sea urchins, lampreys, sharks, reptiles, mammals. (Note that this is not true, it’s no more than a sloppy shorthand for common ancestry, but it’s a handy shorthand for this purpose.  See a phylogenetic tree here.) Mammals have a form of adaptive immune system that includes T lymphocytes and antibodies, and at first glance this whole complex system arose, almost fully-formed, in sharks.1

This has always amazed me, because an adaptive immune system doesn’t work in isolation; the pieces don’t work alone. You need all kinds of moving parts — all the complex molecular pieces that chop and snip DNA to form T cell receptors and antibodies, all the multiple parts of a thymus that screen T cells for functional and safe receptors, the MHC molecules that the receptors see and all the pieces that snip and shuffle around peptides for that system, the spleen and lymph nodes that let lymphocytes interact with other cells, — and it seemed that all these pieces abruptly appeared and put themselves together, like a fine watch, in one evolutionary blink.

When I first learned about this, some 15 or 20 years ago, I told myself that this was an illusion, that once more species were looked at we’d see the history of these moving parts in other common ancestors. Of course, this is exactly what’s happened since then. We see accidental, random parts in sea urchin genomes (I talk about that here) and we see other bits and pieces arising in lampreys and hagfish (in the links at the top).

So in reality, the adaptive immune system didn’t arise all that suddenly after all; the pieces gradually were added over a hundred million years or more, sometimes purely by chance, sometimes for other purposes altogether, and sometimes as components of a prototypic immune system that acted as a foundation for the whole shark thing.2

So that’s the first part of the background: In lampreys, which diverged from the mammalian lineage maybe 450 million years ago, we see many of the pieces of a mammalian adaptive immune system. There are cells that look a lot like lymphocytes, there is something that looks like a spleen. But, as I say, there are none of the familiar pieces that we think of as an adaptive immune system. Lampreys flatly do not have our adaptive immune system:

Nevertheless, the cardinal elements of adaptive immunity, namely Ig, TCR, RAG1 and 2, and MHC class I and II, were conspicuously absent.3

Lamprey "antibody"
Lamprey variable receptor with bound antigen4

But step back a little, and look a little deeper, and we see some familiar parts. Lampreys do, in fact, have variable receptors, just like T cell receptors and antibodies, and those receptors are made by chopping and shuffling genome DNA, just like TcR and antibodies, and are expressed in their lymphocyte-like cells, and some are secreted (like antibodies and B cells) and some are cell-associated (like T cell receptors).

And here’s the other amazing thing: At the molecular level, the lamprey receptors are completely unlike T and B cell receptors. The lamprey lineage came up with a completely different system that allows them to do pretty much the same thing as the shark lineage. Their receptors are different kinds of molecules, and the system that shuffles the genomic DNA is different. 5 Yet, the functional end product is the same — a system that has immunological memory. An adaptive immune response, that’s quite alien to our own, but that works pretty damn well.

Although the Ig-based and VLR-based adaptive immune systems in jawed and jawless vertebrates use different genes and assembly mechanisms, both systems generate diverse repertoires of anticipatory receptors capable of recognizing almost any Ag through the combinatorial assembly of large arrays of partial gene segments. The development of clonally diverse lymphocytes allows for Ag-specific responses and memory, which are lacking in innate immunity.3

There is still a lot we don’t know about lamprey immunity (how does it present self-reative receptors, with no thymus?) but what we do know is just so amazing, I’m completely fascinated by it. It beautifully illustrates two of the basic features of evolution — building on previous structures, whether related or not; and alternate solutions to the same problem. Herrrin and Cooper have a short and dense, but very interesting, review, 3 that prompted this particular post.


  1. That is, in the common ancestor of sharks and mammals, to use a slightly less-sloppy terminology.[]
  2. And of course, the system has continued to evolve. The mammalian system is remarkably similar to the shark in broad strokes, but it’s also very different in many ways.[]
  3. Herrin, B., & Cooper, M. (2010). Alternative Adaptive Immunity in Jawless Vertebrates The Journal of Immunology, 185 (3), 1367-1374 DOI: 10.4049/jimmunol.0903128[][][]
  4. B. W. Han, B. R. Herrin, M. D. Cooper, I. A. Wilson (2008). Antigen Recognition by Variable Lymphocyte ReceptorsScience, 321 (5897), 1834-1837 DOI: 10.1126/science.1162484[]
  5. Though there are some common pieces that hint at a common ancestor of the two systems, maybe.[]
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