Cockles, and Mussels

Looking further at that  article about a transmissible cancer in clams, it appears that cell line infections are common in bivalves – oysters, cockles, mussels – without being recognized as such until now.  Could be true in other filter-feeders – sponges, brachiopods, etc. Gills might also be a transmission mechanism- so cell line infections may be a general problem for oceanic organisms.

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A common variant linked to chromosomal errors

A new paper in Science (Rajiv McCoy as main author) says that there’s a genetic variant, probably in the gene PLK4, that substantially increases the fraction of embryos with screwed-up chromosomes.  Mothers with the high-risk genotypes apparently have fewer embryos that survive to 5 days. And, oddly enough, the variant causing this is quite common – spread all over the world, in the 20-45% frequency range.  It looks as if it’s the product of a old partial selective sweep in humans ( Neanderthals don’t seem to have had it).  PLK4 regulates centriole duplication, a key component of the centrosome cycle.

So far so good – a nice piece of work. But then they try to explain it.

Their idea is that reducing fecundability was itself advantageous, because it obscured paternity. I don’t believe a word of it.

First realize that the selective cost isn’t as high as you might think: generally people could only feed a couple of kids anyhow. Taking an extra month or two to start that kid is a cost, but not as big as the fraction of embryos lost might make you think. On the other hand, there would be a big selective advantage for a genotype that was resistant to these pro-aneuploidy alleles..

I’d bet on meiotic drive. Intragenomic conflict.  Not crazy for a gene involved in the centrosome:  centrosome genes associated with meiotic drive have been seen in Drosophila.

If the aneuploidy allele was transmitted to, say, 54% of the offspring of a heterozygote mother, it could work.

There would of course be a net disadvantage in homozygotes, because A. the aneuploidy is worse and B. the allele is competing with itself – so winning is impossible.

With a net disadvantage in homozygotes, the sweep never reaches 100%.

Posted in Genetics | 23 Comments

Cell Line Infections, or, my dog has no bones

[ I wrote this back in 2002]

Host cell lines are an entirely new class of disease-causing organism. They are strange and unusually disgusting, and if you read this you may end up showering in Lysol for the next few weeks. Consider yourself warned.

A host cell line is a microorganism that was until fairly recently a part of some higher organism – roughly speaking, a contagious cancer. We know of one good example, transmissible venereal tumor, also known as canine venereal sarcoma or Sticker’s sarcoma, a contagious neoplasm of dogs. It is not contagious in the same sense as liver or cervical cancer, which are (usually) consequences of viral infections. In those cases, it is the virus that is infectious; here it is the cancer itself. Viable cells become engrafted onto mucous membranes and grow in the new host animal. Transmission is usually sexual, but licking or inhaling sometimes causes oral or nasal tumors. Chromosomal and genetic studies indicate that all cases of TVT share a common origin – all share a particular pattern of chromosomal rearrangement and carry characteristic insertions.
TVT is a real disease that affects a significant number of dogs in the tropics and subtropics. It is not always fatal; in most cases, especially in adult dogs, it regresses after a few months. This kind of spontaneous remission is very rare in conventional forms of cancer.
TVT is also very, very strange. In fact it is astonishing. It sounds logical enough, and one can see how it might happen. Cancer cells are probably selected for low immunological visibility, and cancer cells that originated on one dog’s mucous membrane might occasionally be transmitted by contact, escape notice by the other dog’s immune system, and grow. Once this happens, natural selection would gradually optimize transmission.
But although the process is not so mysterious, the implications are vast. First, we have here the most abrupt evolutionary transition known, a jump from mammal to one-celled organism in a single step. For this transmissible tumor, also called canine venereal sarcoma, is in every sense an independent infectious organism, just as much so as Salmonella typhi or Plasmodium falciparum. It reproduces and metabolizes. Although descended from dogs, it is genetically different from dogs, with a different chromosome number (57 rather than 78), due to extensive chromosomal rearrangements. Since it cannot, as far as we know, exchange genetic material with dogs, it is a new species.

Although its phenotype differs considerably from dogs (no brain, no bones, no eyes, no fur, asexual) classification by descent clearly implies that it is a canid and mammal – certainly the most unusual mammal ever discovered. And classification by descent is the right way to go. If you try to classify animals by similarity of surface appearance, you’ll get into trouble. Recent molecular work shows that elephant shrews, elephants, manatees and aardvarks descend from a common African ancestor. An elephant shrew looks a lot like a shrew or rat, but it is more closely related to an elephant. In the same way, the organism causing canine venereal sarcoma is more closely related to a wolf than a fox is, even though you need a microscope to examine it.
Are there other cell line infections? There is at least one, a contagious leukemia in hamsters. HeLa, a long established experimental human cell line, comes pretty close. It originated as a cervical adenocarcinoma in Henrietta Lacks in 1951, and is wildly successful in the limited niche of tissue culture. It has repeatedly outcompeted and replaced other cell lines via cryptic contamination, ruining a great deal of research in the process. At one point, most of the supposedly different human cell lines used were actually HeLa. Leigh Van Valen and Virginia Maiorana have pointed out that HeLa should logically be considered a separate species. and they’re completely correct. I think that TVT, as the cause of a common natural disease, is even more interesting, since its existence in nature suggests that there may be many such cell-line species. The existence of a whole new category of disease organism, of the same level of generality as bacteria or viruses or protozoa, would be of the first importance.
Why do I think that there are probably many other host cell line infections? First, TVT exists in dogs, and dogs are really not all that unusual, except for their close association with humans. That close association probably does not make dogs especially susceptible to this kind of infection, but it greatly increases our chance of noticing it. We know much more about the diseases of domesticated animals than we do about diseases of wild species. The transmission modes for TVT are not particularly unusual and should work in many species. For all we know, many species have one or more cell line infections.

Infectious cell lines may not be very noticeable – it seems possible that they might pass for host cells. Certainly people have not been looking for such things. In addition, diseases caused by infectious cell lines would not have to look or act anything like cancer. TVT itself hints at this; even if you think of TVT as a cancer, forgetting its infectiousness, it’s pretty unusual, mainly because of that high rate of spontaneous remission.

The right way to understand this is by considering the evolutionary pressures on an infectious cell line, which are very different from those that shape ordinary, non-transmissible cancers. In conventional cancers, the cells that grow the fastest win out – if you call being the first to kill the host winning. The amount of possible evolutionary change in a nontransmissible cancer is limited, since all such change must occur within one host’s lifetime.
Infectious organisms, including transmissible cell lines, often do best by adopting more moderate strategies. ‘Grow like mad’ is often not the best approach; it is likely to harm or kill the host, reducing opportunities for future transmission. Infectious organisms usually adopt strategies that involve slower-than-maximal reproduction, allowing extended host survival. Infectious organisms that depend on host mobility for transmission, rather than some vector, are especially likely to allow prolonged host survival. Thus we see that some infectious diseases (like the rhinoviruses that cause the common cold) are mild and never kill the host, some persist indefinitely while doing little harm to the host (Herpes I), others, like HIV, kill quite slowly. Diseases caused by long-established cell line infections might look like any of these, but would probably not kill quickly. Diseases caused by long-established cell lines should look more like other transmissible diseases (tuberculosis, say) than cancer.
We can make some predictions about the likely characteristics of cell line infections. First, infectious cell lines would grow fairly slowly. Viruses and bacteria have doubling times as low as 20 minutes, but cells of higher organisms take considerably longer. They would probably not be very hardy. Some bacteria and viruses can survive for long periods in the exterior environment – anthrax spores can remain viable for decades – but it is hard to see how an infectious cell line could do the same, unless it has existed for a long time and diverged very far from its ancestral cancer.
Even though infectious cell lines would probably not be very durable, there are still a number of possible transmission routes. From the example of TVT, we already know that sexual and oral transmission are both possible. From what we know of venereal disease, sexual transmission usually implies vertical transmission as well. Respiratory transmission is probably possible, since aerosols can transmit HeLa. If the host cell line has existed for a long time, long enough for substantial adaptation, we might see vectorborne transmission by arthropods. Aquatic organisms, especially filter feeders like clams, might manage to transmit cell line infections short distances through water (and there is a contagious leukemia of clams that looks very suspicious).
Cell line infections would probably not be susceptible to antibiotics; since antibiotics take advantages of the differences between host and parasite, things like the bacterial cell wall or the bacterial ribosome. Here those differences would be very small, and it would be difficult to find chemotherapeutic agents that hit the host cell line infections lots harder than the host. This could be an important epidemiological clue.
Cell line infections may be capable of very complex manipulations, since they start out with the ability to make every hormone and signal chemical. In other words, they start out knowing how to push your buttons. They might be able to trick the immune system or change your behavior in ways that maximize transmission.
If cell line infections are reasonably common, it might be that immunological rejection of foreign tissue, which so complicates organ transplants, is a necessary function rather than a side-effect.

The most important practical point is that those few people who are actually looking for causes of diseases should consider this possibility. There are diseases that look as if they might be infectious where no causative organisms has ever been found – diseases like sarcoidosis. They might be caused by some disease that started out as your second cousin Frank. It might be older than that – we might find surviving Neanderthal cell line diseases.

Gregory Cochran

P.S. There are some other organisms and diseases that have some similarities to cell line infections. A number of parasitic organisms have lost so many nonessential functions that it is almost impossible to tell what they once were by any methods other than molecular biology. For example, the organism that causes ‘whirling disease’ in trout is a degenerate jellyfish. And there are known examples in humans where cells from someone else can exist for long periods and, at least occasionally, cause trouble. Many women who have had sons will have a few XY leukocytes, even decades later. We routinely irradiate blood transfusions, because when we didn’t, in rare cases totipotent leukocyte cell lines (usually from close relatives, immunologically similar) proliferated in the transfusee and killed him.

[ 2015] We now know of another example, DFTD, (Devil facial tumour disease), that afflicts Tasmanian devils, threatening them with extinction. And there’s a paper just out in Science confirming that contagious clam leukemia is also a cell line infection.  Told you so.
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Ain’t gonna study war no more

Military history has almost vanished from academia, especially in ‘elite’ institutions. This is probably related to that strange Bellesiles incident, and the trend toward Kumbaya models of prehistory in archaeology and anthropology.  It’s not just that academic historians don’t publish on war – they don’t know anything about it themselves, and they have contempt for anyone who does. A colleague asked John Lynn if military historians wrote in crayon; one head of a history department called military history “of interest only to hormone-driven fraternity boys.”

Pride in ignorance: that’s hard for me to understand. There are subjects that don’t interest me, like baseball stats, where not knowing doesn’t much bother me – still, ignorance of sabermetrics is nothing to be proud of.  Putting war in that category strikes me as deeply crazy. Like the bad man says, you may not be interested in war, but war is interested in you.

Unfortunately, some of the remaining military historians try to placate the history establishment by reframing the subject in ways that cater to establishment interests – you know, writing articles like “Dykes at Kursk”, or discussing the role of ‘people of color’ in the wars of the Diadochi.  Sucking up to pinheads.


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Back by Popular Demand


One of the interesting things about the growing enthusiasm for transgenerational epigenetics – the kind where your grandfather was poor or discriminated against which somehow makes you terrible at algebra today, except not if you’re Korean – is that has been bottom-up.  It has not been driven by convincing experimental results – of course there haven’t been any.  Instead, it was an idea that appealed: more and more people in certain circles talked about it, convinced each other by the most powerful of all arguments (“Wouldn’t it be nice if ?”) and that eventually drove bullshit experiments and publications.  Looking at Google’s Ngram Viewer, it looks as if this particular mental fungus sprouted around 2003.

There may have been a particular article or book that started this wave of nonsense, but I haven’t found it yet. Even if there was, it only succeeded because the soil was fertile. It was a bad idea whose time had come.  One can understand some of the motivation: gaps persisted and persisted in spite of many costly interventions. It must have been frustrating.

Back in 1940, the Soviet powers that be wanted more wheat (and more dead kulaks, of course) .  Today, our most desired product is excuses.

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Scanners Live in Vain

There is a new paper out in Nature Neuroscience,  mainly by Kimberly Noble, on socioeconomic variables and and brain structure:  Family income, parental education and brain structure in children and adolescents. They found that cortex area went up with income, although more slowly at high incomes.  Judging from their comments to the press, the authors think that being poor shrinks your brain.

Of course, since intelligence is highly heritable, and since people in higher social classes, or with high income, have higher average IQs (although not nearly as high as I would like), you would expect their kids to be, on average, smarter than kids from low-income groups (and have larger brains, since brain size is correlated with IQ) for genetic reasons.  But I guess the authors of this paper have never heard of  any of that – which raises the question, did they scan the brains of the authors?  Because that would have been interesting.  You can actually do microscopic MRI.

Even better, in talking to Nature, another researcher, Martha Farah,  mentions unpublished work that shows that the brain-size correlation with SES  is already there ( in African-American kids) by age one month!

Of course, finding that the pattern already exists at the age of one month seriously weakens any idea that being poor shrinks the brain: most of the environmental effects you would consider haven’t even come into play in the first four weeks, when babies drink milk, sleep, and poop. Genetics affecting both parents and their children would make more sense, if the pattern shows up so early (and I’ll bet money that, if real,  it shows up well before one month);  but Martha Farah, and the reporter from Nature, Sara Reardon, ARE TOO FUCKING DUMB to realize this.

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So you’re thinking of being a traitor

I was just reading something by Freeman Dyson, a review of a biography of Bruno Pontecorvo.  He explains that technical spies, like Pontecorvo or Klaus Fuchs or Ted Hall, are unimportant because the Soviet Union had plenty of first-rate scientists already, people like Yuri Khariton and Zeldovich and Sakharov, and would have eventually gotten to the same place anyhow.  He thinks that people like Hall only accelerated the Soviet bomb program by two or three years. But tactical spies, people like Aldrich Ames or Kim Philby , who burned fellow agents and got them killed – they’re quite naughty.

So I guess being a atomic spy in the service of the Soviet Union was almost a peccadillo.  Right-thinking people certainly want to think that, since so many of them were sympathetic to Uncle Joe (‘ he rolls the executions on his tongue like berries’ ) and his antics. Of course, right-thinking people are always wrong.

Gee, what happened in those two or three years? Anything bad? Anything that wouldn’t have happened if Stalin was Bombless?  The Korean War, certainly.  Heard of it? Moreover, those technical spies saved the Soviets money as well as time – we explored all the possible approaches to manufacturing fissionables in the Manhattan Project, most of which were expensive failures, but the Soviets didn’t have to.  Their resources were limited: this helped.  Their first bomb was made from Los Alamos engineering blueprints (thanks, Ted Hall !)

Usually,  you have to be careful not to be too hard on public intellectuals, since they’re not very smart and don’t know jack about anything. You really can’t expect anything from them.  Dyson, however, is smart – very smart –  actually knows some things, and has accomplished a lot.  But he’s still utterly full of shit, when it comes to making excuses for ‘his kind of people’.

Let me make a few suggestions for the next crop of foolish scientists considering aiding the next noxious ism. I think there’s a ‘due diligence’ principle – maybe, just maybe, before  changing sides, you really need to check if the guys you’re aiding are tyrants and mass murderers,  And if they are, that’s a bad thing, not a proof of how serious they are. Check before you defect.  Pontecorvo didn’t check: I think he was a a damn fool, worse than stupid.  He came to agree: “The simple explanation is this: I was a cretin,’ he said. ‘The fact that I could be so stupid, and many people close to me should have been quite so stupid . . .’ The sentence was left unfinished. Communism, he went on, was ‘like a religion, a revealed religion . . . with myths or rites to explain it. It was the absolute absence of logic.’ ”

I know that means reading something other than Nature or Phys Rev.  It might even mean listening to the Lithuanians in the neighborhood bar as they complain about their cousins being shot – but I don’t think that’s asking too much.  Parenthetically, why is it that intellectuals feel attracted to monsters like Stalin or Lenin, but hardly ever become agents/disciples of Switzerland or Canada or Uruguay?  Nice countries finish last?

Perhaps nothing can really be done: it may be that a high fraction of the psychological types that produce scientific advances are just silly people, without a bit of common sense.  Born that way.  Maybe we could work hard at making executions more certain, frequent and terrifying:  in a better world, Ted Hall would have shit in his pants at the mere thought of committing treason.

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