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.