Xenotransplantation and Swine Flu

Trying to solve the organ transplant shortage using pig organs was both a really good idea and a really bad idea. It was good because a pig's body is reasonably close to ours in terms of size, biology and organ-loading (and because pigs are omnivores, like us) ... and bad because of the virus problem that some people didn't like talking about.

There are three main reservoirs of "foreign" viruses that sometimes cross over into the human population and catch our immune systems unawares - other primates, livestock, and birds. Primates tend to be blamed for origins of the the AIDS virus, the 1918 "Spanish Flu" outbreak that killed between fifty and a hundred million people is sometimes reckoned to have crossed over from birds, and when mammalian livestock is concerned, the culprit is usually assumed to be pigs.

When a disease like this crosses over from a pig or a chicken, we sometimes get a bit disgruntled in the West and mutter that these poor agricultural communities really shouldn't be living in such close proximity to their animals, but for years we've been planning on going one better. Transplanting pig organs into people means that living pig tissue is in as intimate contact with human tissue as its possible to be - actually snuggled up together subdermally and sharing a common blood supply. In Darwinian terms, if you wanted to encourage pig viruses to evolve so that they could thrive in a human environment, this is exactly how you'd do it, and if you were a genocidal mad scientist intent on "accidentally" killing millions of people in a cost-effective manner, without actually hiring weapons research specialists and running the risk of being spotted, then this'd be a great way to do it.

Now, you might think that we could breed a "special" population of guaranteed "disease-free" oinkers in laboratory conditions, to ensure that any transplant organs are kept squeaky-clean, and to minimise the risk as long as the organ recipients were then kept well away from any live pigs (to protect both the human and pig populations) – some researchers were supposed to be setting up special facilities for breeding "special" pigs, perhaps with a bit of gene-manipulation to make the immune-system rejection problems less severe.

Snag is, it turns out that you can't breed "clean" pigs.
Normally, the DNA in your cell nucleii codes for proteins that get used within the cell, and for RNA that moves out of the cell nucleus to do Very Useful Things in other parts of the cell. DNA also copies itself during cell division. Viruses are often RNA-based, and usually insert themselves into a cell, where they tell the cell to make more RNA-based viruses.
But RNA retroviruses run the cell's usual DNA-RNA mechanism backwards – they write DNA versions of themselves into the cell nucleus ("reverse transcription"), and from that point onwards, the cell's own nucleus generates new viral RNA.
If a retrovirus infects a mammalian egg cell or a sperm-producing cell, and those cells produce viable offspring, then those offspring inherit the virus as part of their genome - it's been written into the DNA of every one of their cells.

Sometimes the inherited virus isn't active, or is corrupted so that it does nothing, or ends up mutating again to do something that's actually useful to the host. If it's active, the individuals who have it will presumably have gene-repression systems and a primed immune system that can deal with it, otherwise they'd not survive long enough to be born. So pigs can carry a payload of porcine viruses in their DNA, and still be perfectly healthy. And they do – it turns out that as farm animals, pigs have been so intensively interbred that it now doesn't seem possible to find a pig that doesn't have a library of piggy viruses already written into their DNA. To encourage those viruses to learn how to infect human cells, all you'd have to do is transplant some living virus-bearing pig tissue into a human, and give that human immunosuppressant drugs to damp their immune system long enough to give the fledgeling viruses a change to get in a good few generations of useful mutation, and – bingo! – you've got yourself a new "alien" human-compatible virus that most human immune systems won't yet recognise.

The xenotransplanation research community were always playing with fire. Getting funding for research that might eventually save thousands or tens of thousands of people's lives (including sick kiddies) is good ... but getting funding for a large-scale xenotransplantation programme that might end up being implicated years later in the deaths of tens of millions would be ... not quite so good. So the ethics watchdogs within the community said that it was important that society as a whole understood the risks and decided consensually to go for xenotransplantation, but when it came to lobbying for funds, the TV news would tend to show pictures of dying children with tubes stuck in them, and impassioned researchers saying that this was necessary to stop people dying ... but forget to mention the risk of a potential associated death toll on the scale of that of World War 2.

So the current swine flu outbreak has probably saved the xenotransplanation community from having to wake up in ten years time and find that their work had been responsible for killin a hell of a lot of people. Their funding bodies probably now know rather more about pig viruses, and will now tend to ask the right questions when someone suggests stitching pig tissue into human recipients. Such as: "But isn't that an insanely irresponsible thing to do?". Since the 2009 outbreak, researchers can no longer pooh-pooh safety concerns by pointing out that nobody on the board has heard of anyone who's actually been hurt by swine flu. Conventional live pig-organ xenotransplanation is probably (hopefully) now a dead field.

Good work can still be done. There are some people now looking at taking pig hearts and dissolving away all the tissue to leave a cartilage skeleton on which human stem cells can be grown, to create a working human-tissue heart. That sounds like a much more sensible idea.

There's just one last question we need to answer. The sites where US researchers were keeping their pigs tended to be secret, to avoid protester sabotage and industrial espionage, and to try to make sure that the pigs were kept free from external contamination of pig or human pathogens. It'd be useful to have a full list of all such sites, to see if any of them had been set up conveniently across the border in Mexico. If there's genuinely not a link between xenotransplantation research and the current swine flu outbreak, then the xenotransplantation community can consider themselves lucky – they dodged a bullet.

Cyclamate Sweeteners Shrivel Your Testicles

Sometimes I notice details that don't quite seem to connect, and it bugs the hell out of me until I eventually find out why.

Some years back, I saw an episode of a detective show (perhaps "Columbo"?), whose resolution hinged on the idea that there was a particular artificial sweetener used in soft drinks in the 1960's that then got withdrawn. That was a bit before my time, but it puzzled me that the writers seemed to assume that the viewer knew about this, but somehow I hadn't heard of it. So I thought I'd look the thing up to see if it was true.
Apparently it was – according to the literature, cyclamate sweeteners appeared in mainstream products before being banned by the FDA in 1969. But a substance doesn't just get banned from food production without kicking up a bit of media discussion, and I was arrogant enough to figure that if I hadn't come across any such discussion then ... there was probably more to this subject than met the eye. My antennae started twitching. Something smelled wrong.

So I looked deeper. The listed reason why cyclamates were withdrawn, according to the first wave of usual sources, was a possible "slightly elevated cancer risk". Again, this didn't smell right – I'd heard a lot over the years about the similar alleged (small, supposed) risk of bladder cancer associated with saccharine, which wasn't banned in most countries, so where had the corresponding discussion about cyclamates gone? There was an cultural anomaly here – the public discussions that ought to have happened seemed to be missing, and I now badly wanted to find out why.

This was long before the days of Google, so in about 1990 I found myself at an outpost of the British Library, crouched over an old green-screen text terminal that had basic online subscription access to a medical research database, and there I found the obvious answer to why industry people didn't discuss cyclamate side-effects. A distinctive three-word medical term, that once heard and explained, you don't tend to forget.

Cyclamates are associated with ITA.

ITA stands for Irreversable Testicular Atrophy.

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Yes, you read that correctly. It seems that if you're a primate, and male, cyclamate sweeteners can cause your balls to progressively shrivel and wither away. Permanently. Researchers don't know why.

So that was it. That was why nobody told the public what they'd discovered, and why the product was taken off the market, using the iffy "cancer" argument as an excuse. It wasn't in the interests of the drinks companies to mention that they'd probably been chemically castrating some of the guys who drank their cola, it wasn't in the interests of the FDA to admit that they'd approved a substance for mainstream use that had been permanently shrivelling the Male American Public's manly bits. It probably also wasn't in the interests of the research community to go around telling outsiders about their part in a major public health boo-boo that many of those outsiders would find difficult to forgive, if they knew about it. But if you bypassed the commentaries and looked up the original research papers, there it was, in stark black-and-white. ITA.

Cyclamate Returns

The story's moved on since then. Some companies really liked using cyclamate as an ingredient – it was cheap, people preferred the taste to saccharine, and it avoided the later nasty public-relations mess associated with Nutrasweet and product safety. And the biochemical/food industry did some digging of their own, and realised that actually, organisations like the FDA might not be allowed to ban cyclamates.

See, the FDA's remit is public health, and the industry lobbyists started arguing that that having permanently shrunken testicles doesn't actually count as a health problem (no matter how angry the owners of those testicles might be if they found out why). It isn't traditionally associated with work disability (unless you're a porn star), and there's no obvious associated reduction in life expectancy, unless you start to guess at factors like depression and impotence-related suicides.

A product that damages the testicles of male customers doesn't obviously kill anybody. In fact (the industry argued), the associated reduction in testosterone in guys with withered testes might even be associated with a statistical reduction in the frequency of certain testosterone-related cancer deaths (for instance, high testosterone is supposed to exacerbate prostate cancer). Since castrati were generally reckoned to have a greater life expectancy than "intact" blokes, there was an argument that the use of their sweetener product might actually extend average male lifespans rather than reduce them. So (the industry argued) not only were the FDA not allowed to use the ITA argument as a reason for banning the product, they couldn't use the weaker "bladder cancer" argument either, unless they could show that the hypothetical life-expectancy reduction due to increased incidence of bladder cancer was expected to be greater than the corresponding LE extension due to reduced male hormone levels. Cyclamates probably weren't "harmful" if you judged "harmfulness" by a number based on medical life expectancy.
A further argument was that if the potential sexual-function-impairment aspects of cyclamates were outside the FDA's remit, then the FDA was not supposed to tell anyone about them in their reports, because it wasn't the job of a government department to use state funding to "bad-mouth" a product by mentioning negative aspects of that product that weren't anything to do with them. The FDA were supposed to shut up.

So now cyclamates are finding their way back into food, and for a few years now, industry groups have been more bullish about lobbying for the FDA ban to be removed. As a page on the National Cancer Institute website delicately puts it:

" A food additive petition is currently filed with FDA for the reapproval of cyclamate. The FDA's concerns about cyclamate are not cancer related. "

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One last point: if you're reading this and feeling smug because you're female ... well, don't.
See, we don't yet know the mechanism by which cyclamates appear to damage and kill off seminal frond tissue, and it may well be that cyclamates might be doing do something similar to the female reproductive system, unnoticed. Atrophied ovarian tissue is going to be more difficult to spot in the lab than atrophied testicles, simply because its not as easy to do a "before and after" weighing comparison with internal organs. We also don't know whether cyclamate's attack on the germ cells might be associated with heritable genetic or epigenetic damage to the reproductive cells that survive. If your guy's taking cyclamate sweeteners, is it damaging his sperm, and affecting any kids that you might have with him, from that sperm? And what happens if you're pregnant with a male child while ingesting a lot of cyclamate? Does the reproductive-tissue-shrinkage effect in adult males have a counterpart that affects the growth and development of that tissue in the fetus?

There are some genuinely nasty possibilities here.