Mystery Rays from Outer Space

I don’t know why I read the ScienceDaily newsfeed, because it drives me crazy every single day.  I had naively thought that whoever massages the press releases they receive would have, maybe, a teeny tiny clue about what’s gone on in the field before, but they seem to have the historic awareness of tree squirrels.  Today’s gem:

It’s a paradox that has confounded evolutionary biologists since Charles Darwin published On the Origin of Species in 1859: Since parasites depend on their hosts for survival, why do they harm them? … The study, published in the early online edition of the journal Proceedings of the National Academy of Sciences, provides the first empirical evidence in a natural system of what’s called the “trade-off hypothesis.

It’s not a “paradox” at all, and while it may “baffle” the marketing department that wrote the press release ScienceDaily regurgitated, it certainly hasn’t baffled evolutionary biologists for a long time.  I’ve talked about this exact subject here:

… if there’s a link between increased transmission and increased virulence, then the balance will not favour the pathogen becoming benign.

Here:

I’ve previously talked about the common misconception that viruses evolve toward benignity. This is usually phrased something like, “Natural selection favours viruses with low pathogenicity/virulence (so they don’t eradicate their hosts)“, or “Viral pathogenesis is an abnormal situation of no value to the virus“. This claim is clearly wrong — “clearly” both through common sense, and through observation.

And here:

I’ve observed before that the common belief that viruses evolve toward avirulence is not particularly true. It’s more accurate to say that viruses evolve toward improved transmission. Some viruses are better transmitted if they let their host survive longer, but other viruses have to be virulent in order to spread. The former may evolve toward reduced (though not necessarily loss of) virulence, but the latter would “want” to maintain stable virulence.

I’m not so much an antibody guy, but of course I’ve heard about catalytic antibodies. Catalytic antibodies bind, with the very high affinity that’s typical of many antibodies, to transition state molecules, stabilizing the transition state and facilitating the chemical reaction. They’ve been around for quite a while (I think the first, or at least first widely-announced, catalytic antibody¹ was described in the mid-1980s) and a fair number of them have been created.

But as far as I know, catalytic antibodies remain a curiosity — a fascinating curiosity, but one without a lot of practical application. Although they can be custom-made and can have great specificity, as enzymes they tend to be really crappy (as you might expect), acting thousands or millions of times slower than “genuine” enzymes. Again, I’m no expert, but it seems that in spite of decades of promise, there hasn’t been much payoff; which is a shame, because the concept is so cool they deserve to make it big.²

Recently, though, there was a paper³ offering a catalytic antibody that actually was therapeutic in a real live animal model. Is this the one where promise actually follows through to reality?

The antibody was raised against a virulence factor, urease, of Helicobacter pylori, the ulcer-causing bacterium. (Urease helps neutralize the stomach acid, so it helps H. pylori colonize stomachs.) The antibody degraded urease reasonably well; and more remarkably, the light chain alone of the antibody was also able to degrade H. pylori urease. I don’t know how common this is for catalytic antibodies,⁴ but it strikes as potentially useful, since the light chain can be more readily synthesized and is probably more stable on its own.

The interesting part was that they treated mice with this — I think the first time catalytic antibodies have been used in vivo. They infected the mice with H. pylori, and then treated them with either the catalytic light chain in buffer, or with buffer alone (they should really have used a control light chain in buffer, though — in general this paper doesn’t strike me as terribly well-controlled when is comes to the animal work, but part of that may be the poor English throughout). The treated mice had about a third as many bacteria in their stomachs as did control mice, suggesting that the antibody actually did some good. Presumably it degraded urease in vivo as it does in vitro, and by inceasing stomach acidity helped reduce the bacterial survival.

This is still far, far from any kind of useful treatment, I think, but it’s a step forward.

1. Pollack SJ, Jacobs JW, Schultz PG (1986) Selective chemical catalysis by an antibody. Science 234:1570-1573.[↩]
2. If I’m wrong, by the way, and catalytic antibodies have achieved a toehold somewhere in medicine or industry, please let me know. As I say, I don’t follow this field all that closely.[↩]
3. Hifumi, E., Morihara, F., Hatiuchi, K., Okuda, T., Nishizono, A., Uda, T. (2007). Catalytic Features and Eradication Ability of Antibody Light-chain UA15-L against Helicobacter pylori. Journal of Biological Chemistry, 283(2), 899-907. DOI: 10.1074/jbc.M705674200[↩]
4. It’s not unique, because the authors say they had the same thing for a previous catalytic antibody they made[↩]

I just got back from Toronto, where I visited the Darwin exhibit at the ROM;¹ the picture above is what my kids look like after being sternly told to stop goofing around.²

Bonus pictures! while I stall on putting up a real post here:

Cap’n Matthew navigates the HMS Beagle through the stormy seas of the ROM	Alex the Albertosaurus

1. Also made it to a ballgame to see my Red Sox lose to the Jays, and the Ontario Science Center for the kids[↩]
2. Yeah, no pictures allowed at the Darwin exhibit. They didn’t shoot me, though.[↩]

Some leaf-cutter ant lineages are more likely to become queens than other lineages; they “cheat”. These lineages are a minority, about 20%, of all leaf-cutter lineages. I’m fine with all that. What puzzles me is this quote:

“The rarity of the royal lines is actually an evolutionary strategy by the cheats to escape suppression by the altruistic masses that they exploit.”

Bill Hughes, quoted in Science Daily News. It’s not a misquote, either; the abstract of the paper in question¹ says essentially the same thing:

The rarity of royal cheats is best explained as an evolutionary strategy to avoid suppression by cooperative genotypes, the efficiency of which is frequency-dependent.

What am I missing here? The strategy is successful because it’s rare, sure. Is he arguing that there is positive selection for rarity, as opposed to a strategy that is selected for when it’s rare, and selected against when it’s common?

1. Proc. Natl. Acad. Sci. USA doi:10.1073/pnas.0710262105
   Genetic royal cheats in leaf-cutting ant societies
   William O. H. Hughes, and Jacobus J. Boomsma [↩]

“We do not understand the world; the world is billions of times more complicated than our minds. You can make a useful contribution to a discussion if you can figure out specifically what it is you don’t understand and try to work on it.”

–Bill James

My papers from my PhD research (not counting previous and subsequent work) have now been cited exactly 1000 times.

When Michael Specter’s article, ”Darwin’s Surprise”, ran in the New Yorker, I had a peevish post complaining about its comments on “junk DNA”.

Now T Ryan Gregory, at Genomicron,¹ is saying what I wanted to say (but that I mangled to the point of incoherence). “Junk DNA” — in spite of lazy journalists’ claims — was not ignored or “dismissed” (the journalists’ favourite word), but was studied with an open mind:

The important message being offered is that there was plenty of research into possible functions or lack thereof in noncoding sequences of all types, and that whichever way authors concluded was based on the evidence available at the time, not ideology.

As well as the whole coherence thing, Genomicron is providing definitive proof with quotes from the literature. Read all about it:
Quotes of interest — 1980s edition (part one).
Quotes of interest — long neglected, some noncoding DNA is actually functional.
Quotes of interest — Nobel Prize special edition.
Quotes of interest — 1980s edition (part two).
and especially
Quotes of interest — pseudogene.

1. And from my old alma mater, though I think I had already left before he started there[↩]

I’m going to the Autumn Immunology Conference in Chicago this weekend. It’s a fairly small, but well-organized and friendly, conference that’s within an easy 3-hour drive,¹ and it gives me a chance to meet other immunologists from the area. ² I went last year and enjoyed it.

One of my students will be presenting; it’s really earlier in the project than I’m really enthusiastic about a presentation for, but the AIC really encourages grad student presentations, and I think students should give as many talks as much as possible, so it’s a good opportunity for him.

Should be a good time.

1. Plus an hour or two of sitting motionless in Chicago traffic[↩]
2. ”The area” being the Midwest, I guess, which is a pretty large area.[↩]

One of the hottest topics in immunology today is the regulatory T cell — thousands of publications, hundreds of reviews. But few if any of the reviews go into any detail on the history of the TReg, instead coughing nervously, shuffling their feet, and hastily pointing out some shiny distracting fact over there. This is probably partly because the authors think everyone already knows the whole sordid story, partly because they don’t want to waste review space on spilled milk, and a lot because the story is embarrassing for those involved.

TRegs are a type of T cell that, as you might guess, regulates the immune response — dampens reactions so that you’re not overwhelmed by the inflammatory response, and reduces the risk of autoimmunity. People and animals lacking TRegs have horrible, often fatal autoimmune diseases. TRegs were defined back in the mid 1990s or so, and the 2000s have seen an explosive growth in the field.

But well before that — starting in the mid-1970s or before — it was known that there were T cells that could regulate (or, as the term was then, “suppress”) immune responses, and in fact much of the basic biology was worked out then. Immunologists identified the suppressor cell and used mouse crosses to identify its mechanism of action. They were able to precisely localize within the genome a molecule that was critical for suppressor T cell activation. This was the “I-J” determinant,¹ and it was localized within the MHC region of the mouse genome. ² Indeed, based on the biology I-J looked like another member of the MHC family. A great deal of work went into characterizing the I-J determinant,³ including the development on monoclonal antibodies against I-J⁴ and preliminary biochemical characterization of the molecule.⁵ In spite of a minority of skeptics, it was a very exciting time.

So, um, it was a little awkward when I-J turned out, well, not to exist. The region that it had been mapped to was sequenced, and, er, there was nothing there. ⁶

We therefore conclude that the I-J gene is not formed by a DNA rearrangement between the I-A and I-E -subregions. … Our data suggest that the genes encoding I-J serologic determinants expressed by suppressor T cells do not map between the I-A and I-E subregions.

‘hem.

Here’s a chart of publications on I-J by year. See what happens in 1984? That is what a balloon popping looking like. For a few years after people still published stuff that had been in their pipelines, but no one was starting anything new, everyone in the field hurriedy left (mumbling to themselves) for greener pastures, and no one entered the field.

What went wrong? I have no idea, to be honest. The people who were working on I-J included a lot of people who are much smarter than I am (including one of my scientific grandfathers, whose Nobel Prize is only the start of his achievements); my schadenfreude includes a great deal of “That could have been me”.

The good news is that after the embarrassed pause, the underlying phenomenon itself turned out to be real and robust. In the mid-1990s people returned to the field (giving the cells a new name to cover over the I-J fiasco), and TRegs have taken off (the chart below shows TReg publications, in green, compared to the suppressor papers from earlier).

One lesson to be drawn from this, by the way, is the difference between science and pseudoscience. A lot of people had invested heavily in I-J. Yet when evidence disproved their hypothesis, the hypothesis was abandoned. What’s more, returning to the data with an open mind allowed the field to generate new hypotheses, test them, and when they turned out to work, to run with them. TRegs today are one of the most promising handles for a bunch of therapies. If this was pseudoscience, people would still be rummaging around the I-J field, attacking the people who disproved it, and rehashing old and useless experiments based on increasingly convoluted explanations for what turned out to be simply wrong.

1. For example, Murphy, D. B., Herzenberg, L. A., Okumura, K., Herzenberg, L. A., and McDevitt, H. O. (1976). A new I subregion (I-J) marked by a locus (Ia-4) controlling surface determinants on suppressor T lymphocytes. J Exp Med 144, 699-712.[↩]
2. For example, Greene, M. I., Pierres, A., Dorf, M. E., and Benacerraf, B. (1977). The I-J subregion codes for determinants on suppressor factor(s) which limit the contact sensitivity response to picryl chloride. J Exp Med 146, 293-296.[↩]
3. E.g. Murphy, D. B., Yamauchi, K., Habu, S., Eardley, D. D., and Gershon, R. K. (1981). T cells in a suppressor circuit and non-T:non-B cells bear different I-J determinants. Immunogenetics 13, 205-213.[↩]
4. Waltenbaugh, C. (1981). Regulation of immune responses by I-J gene products. I. Production and characterization of anti-I-J monoclonal antibodies. J Exp Med 154, 1570-1583.[↩]
5. Asherson, G. L., Watkins, M. C., Zembala, M. A., and Colizzi, V. C. (1984). Two-chain structure of T-suppressor factor: antigen-specific T-suppressor factor occurs as a single molecule and as separate antigen-binding and I-J+ parts, both of which are required for biological activity. Cell Immunol 86, 448-459.[↩]
6. Kronenberg, M., Steinmetz, M., Kobori, J., Kraig, E., Kapp, J. A., Pierce, C. W., Sorensen, C. M., Suzuki, G., Tada, T., and Hood, L. (1983). RNA transcripts for I-J polypeptides are apparently not encoded between the I-A and I-E subregions of the murine major histocompatibility complex. Proc Natl Acad Sci U S A 80, 5704-5708. Also, Davis, M. M., Cohen, D. I., Nielsen, E. A., Steinmetz, M., Paul, W. E., and Hood, L. (1984). Cell-type-specific cDNA probes and the murine I region: the localization and orientation of Ad alpha. Proc Natl Acad Sci U S A 81, 2194-2198.[↩]

OK, maybe it’s not quite as important as a cure for cancer. But it’s close.

StupendousMan’s wins prediction for Yankees and Red Sox, showing one-sigma uncertainty, as the 2007 season progressed.

(Last night the Boston Red Sox clinched their first American League East Division Championship¹ since 1995.)

1. That would be baseball.[↩]