Genetically Modified Pigs: A Potential Solution to the Organ Shortage?

Image from OpenArt - not so good at signage as you see.

An experiment has just been carried out whereby a man with advanced kidney disease has been given the kidney of a genetically-modified pig. He has been discharged from hospital: we await developments.

So how does that work? I asked Gemini for a tutorial article.

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Genetically Modified Pigs: A Potential Solution to the Organ Shortage?

The lack of available organs for transplant is a critical issue impacting countless patients worldwide. Genetically modified pigs are emerging as a possible solution, offering a new source of organs that could revolutionize the field of transplantation. By making specific changes to pig genes, scientists are working to create organs more compatible with the human immune system and minimize the risk of disease transmission.

These modifications address two key challenges: rejection and disease transmission. First, scientists target specific sugar molecules on pig cells that trigger a strong rejection response in humans. Using techniques like CRISPR, they remove the coding for these sugars, making the organs appear more human-like and reducing the risk of rejection. Additionally, they introduce coding for human regulatory proteins into the pig genome. These proteins help the recipient's body better accept the transplanted organ.

Secondly, researchers focus on minimizing the risk of transmitting animal viruses to humans. Pigs carry endogenous retroviruses that could potentially infect transplant recipients. To address this concern, scientists are developing pigs with inactive retroviral genes in their DNA.

While promising, this technology faces several hurdles before widespread use. The field is still in its early stages. Initial clinical trials are underway to assess the safety and function of pig organs in a small number of participants. Even after successful trials, obtaining regulatory approval from organizations like the FDA can be a lengthy process, taking several years.

Scaling up production of genetically modified pigs for transplants will also require time and resources. Herds need to be established, breeding protocols optimized, and proper facilities built to maintain a clean and controlled environment. Additionally, a robust system for matching pig organs to recipients based on factors like blood type and size needs to be developed.

Given these steps, widespread availability of pig-to-human transplants is likely several years away, with estimates suggesting a timeframe of 5 to 10 years.

There's another challenge to consider: even with a mature process, genetically modified pigs wouldn't entirely eliminate the waitlist problem. Since the genetic engineering happens at the foetal cell stage, the pigs require sufficient time to grow organs to a suitable size for transplantation. This growth period, estimated at least 6 months, means patients in critical need of immediate transplants might not benefit from this technology.

However, the potential of xenotransplantation using genetically modified pigs remains significant. This approach has the potential to offer a new lifeline to patients who would otherwise not survive long enough for a traditional human donor organ. Researchers are also actively exploring methods to accelerate pig organ growth, which could further revolutionize organ transplantation and save countless lives.

Using gene drive for vermin control

Controlling 'vermin' with gene drive technology is both interesting .. and a possible fount of unintended consequences.

From The Telegraph:

"There are thought to be more than 10 million rats living in Britain and pest control is estimated to cost the UK around £1.2 billion each year.

The technique suggested for rodents is known as ‘x-shredding.’ Male mammals have both an ‘x’ and ‘y’ sex chromosome, while females need two ‘x’ chromosomes.

The scientists want to insert ‘x shredder’ code into the DNA of male rats which would destroy the ‘x’ chromosomes in their sperm, meaning they could only pass on a ‘y’ chromosome, so their offspring would never be female. With fewer and fewer females over time, the population would have to decline."

Here's an example, starting with sixteen rats, 8 male and 8 female, in population equilibrium. One of the males is a mutant with the gene drive. We assume, for clarity and simplicity, that the mutated males outcompete normal males and always 'get their gal' preferentially.

The population goes extinct in five generations. Initially the population exhibits an exponential increase in mutant males from a low base; in the terminal phase the process is dominated by the ever-decreasing number of females, and - no doubt - tremendously elevated inter-male aggression.

According to Wikipedia,

"Since it can never more than double in frequency with each generation, a gene drive introduced in a single individual typically requires dozens of generations to affect a substantial fraction of a population.

Alternatively, releasing drive-containing organisms in sufficient numbers can affect the rest within a few generations; for instance, by introducing it in every thousandth individual, it takes only 12–15 generations to be present in all individuals.

Whether a gene drive will ultimately become fixed in a population and at which speed depends on its effect on individuals fitness, on the rate of allele conversion, and on the population structure.

In a well mixed population and with realistic allele conversion frequencies (≈90%), population genetics predicts that gene drives get fixed for selection coefficient smaller than 0.3; in other words, gene drives can be used not only to spread beneficial genetic modifications, but also detrimental ones as long the reproductive success is not reduced by more than 30%. This is a great contrast with normal genes, which can only spread in large populations if they are beneficial."

There are of course issues:

• Mutations: It is possible that a mutation could happen mid-drive, which has the potential to allow unwanted traits to "ride along" on the spreading drive.


• Escape: Cross-breeding or gene flow potentially allow a drive to move beyond its target population.


• Ecological impacts: Even when new traits' direct impact on a target is understood, the drive may have side effects on the surroundings.

In particular, natural genetic variation may prevent the drive 'taking' in some males; as a consequence a resistant population may soon emerge. It's been stated that the biggest danger with a gene drive is that it just won't work at all. There is talk of targeting several loci in parallel.

Something phenomenologically similar to a gene drive is at work in human populations (such as India, China) where female foetuses have been selectively aborted. But the numbers involved are well below population-lethal.

Domestic servants: a modest proposal

I have fond memories of our Roomba, spinning mindlessly around our previous house, unable to empty itself and needing help to escape from under the bed. Didn't work in our current home - carpets too thick.

We're as far as ever from artificial general intelligence (AGI). But why try to solve a thousand problems of mental and physical agility when biology has already done the work for us over 400 million years?

"Wait!", I hear you say. Domestic servitude died out with the Edwardians. Besides, the idea of all those servants observing and judging your every move. It's so creepy. No privacy. It's like your home isn't your own.

But that was before CRISPR ...

"She paused. "Just out of curiosity, what's planned fo' the serfs along these lines?"

He relaxed. "Oh, much less. That was debated at the highest levels of authority, an' they decided to do very little beyond selectin' within the normal human range.

"Same sort of cleanup on things like hereditary diseases. Average height about 50 millimeters lower than ours. No IQs below 90, which'll bring the average up to 110. No improvements or increase in lifespan so they'll be closer to the original norm than the Race.

"Some selection within the personality spectrum: toward gentle, emotional, nonaggressive types. About what you'd expect."

If they like serving you, can it really be slavery?

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More about the Draka.

The Outstanding Leader is unwell ..

The BBC website reports:

"The half-brother of North Korean leader Kim Jong-un has been killed in Malaysia, South Korean and Malaysian sources say.

Kim Jong-nam, 45, is said to have been targeted at the airport in Kuala Lumpur, the capital. A source close to the Malaysian PM's office told the BBC that Mr Kim was killed in the city, saying his body was now undergoing an autopsy. Kim Jong-nam is the eldest son of former North Korean leader Kim Jong-il."

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The US President Mr Trump says 'something will be done' about North Korea's somewhat provocative ballistic missile tests. Perhaps one imagines a pre-emptive strike on military facilities?

Easily done, but it's hard not to see the Chinese reacting badly.

Something a little more subtle is needed. Some virus, engineered to attach to cells expressing a certain genotype. Thanks to CRISPR, that kind of virus-editing seems quite practicable. A weaponised flu variant should do it.

How to get a copy of the Dear Leader's genome? You can go a long way with a half brother.

The other half of the mission is transportation. The US authorities should not be relying on a pandemic. A long range stealth-drone delivering a miniature RPV close to the OL should do it: something disposable and wasp-like.

Send a swarm: only way to be sure.

What are the chances the CIA has this mission design in front of the President as we speak?

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Greg Cochran was writing about jihadis, but the principle seems to apply.

When well-intentioned people write bad things

It's not that Matt Ridley hasn't got form. There's a veneer of political correctness which seems to stick to public-intellectual science-writers; they persist in writing cosy, comforting pieces they must know to be misleading, even untrue.

Today, Ridley has an op-ed piece in The Times. "Gene editing isn’t a slippery slope to eugenics", trying to rehabilitate the notion of eugenics.  This is opportune given the dysgenic features of advanced Western countries (relaxed selection leading to mutational load, & the idiocracy stuff), combined with the ameliorating possibilities of genetic engineering.

Ridley starts with the correct statement that eugenics is bad when coercive. State-controlled reproduction is oppressive whether it's China's one-child policy, India's compulsory sterilization or - that old favourite - the disreputable practices of Nazi Germany.

So few problems with his first point:

"First, the essence of eugenics was compulsion: it was the state deciding who should be allowed to breed, or to survive, for the supposed good of the race. As long as we prevent coercion, we will not have eugenics. Our politics would have to change far more drastically than our science."

His second point is more dubious - reassuring cant, some might call it. Artificial insemination with the eggs or sperm of strangers is not what most couples want - they made their own eugenic selection when they chose their partner.

"The second reason we need not fear a return of eugenics is that we now know from 40 years of experience that without coercion there is little or no demand for genetic enhancement. People generally don’t want paragon babies; they want healthy ones that are like them. At the time test-tube babies were first conceived in the 1970s, many people feared in-vitro fertilisation would lead to people buying sperm and eggs off celebrities, geniuses, models and athletes. In fact, the demand for such things is negligible; people wanted to use the new technology to cure infertility — to have their own babies, not other people’s. It is a persistent misconception shared among clever people to assume that everybody wants clever children."

But what if their own child-to-be could be tweaked a little? Or there could be a little bit of selection amongst all their possible children? This is already pretty popular for genetic disease screening; and rightly so.

And then we descend to the plain wrong.

"The more recent discovery that traits such as intelligence are caused by the complicated interaction of multiple genes of small effect means that it is anyway going to be virtually impossible to decide what genetic recipe to recommend to somebody who wants a clever child, or a good-looking one, or an athletic one. By contrast, the genetic changes that cause terrible afflictions such as Huntingdon’s disease or cystic fibrosis are singular and obvious. Selecting embryos that lack such traits, or editing the genes of people so that they are born without carrying such traits, will always be much easier than selecting genetic combinations that might, in the right circumstances and with the right upbringing, lead to slightly higher IQ. Cure will always be easier than enhancement."

We know that embryo selection on as few as ten fertilised eggs could span an IQ gap of ~11 IQ points. That would boost Caucasian populations to the level of the Ashkenazim in one generation. And not a CRISPR in sight.

There is little reason to believe that genetic engineering of many hundreds of SNPs wouldn't be possible within two generations, resulting in significant trait alterations on any reasonably-heritable trait - which is most of them.

We're talking height, health, athletic ability, musicality, personality .. and of course IQ here.

So, Matt, it's not going to be so hard and, trust me, they'll all be jumping at it once it's safe and cheap.

And you must know this. So what's with the 'reassuring' lies?

Nuke 'em!

From Wikipedia:

"Gregory M. Cochran (born 1953) is a physicist and adjunct professor of anthropology at the University of Utah, known for hypotheses in evolutionary medicine and genetic anthropology. He argues that cultural innovation resulted in new and constantly shifting selection pressures for genetic change, thereby accelerating human evolution. He is co-author of the book 'The 10,000 Year Explosion'."

In a typically curmudgeonly post, Cochran imagines a robust response to jihadists, over at West Hunter.

"Now and then I contemplate the possible outcomes if the United States got really, really angry, say at jihadists, if they went too far and struck a nerve. Crazed fury. Jihadists seem to think that enraging the western powers is strategically sensible, but they might be wrong. I’m not talking about little things like the invasion of Iraq or Afghanistan: no, I mean really angry. You should picture Uncle Sam turning green and bursting out of his Uncle Sam suit ... .

"There’s the old reliable, nuclear weapons. There wouldn’t be a lot left of the Arab world, especially when you consider little tactical enhancers like blowing up the Aswan Dam, or nuking a nuclear reactor. You could simply drop enough medium-life-time radioactive dust to make a region uninhabitable for months, or years, or decades, which could make the Haj pretty difficult.

"Even semi-conventional war could become lot more intense: we haven’t done fire raids lately, but we still can (B52s can carry a huge payload). It’s hard to make laser weapons work for most purposes (atmospheric transmission) – but it’s easy to make ones that blind. We’re working on smart bullets: right now you have to fire thousands per hit, but that’s going to change.

"Nerve gas? effective.

"Germ warfare? Amazing things are now possible: we could probably tailor agents to hit particular ethnic groups (there is always leakage: I’m not saying that we wouldn’t get our hair mussed.) . They could kill – swiftly, or agonizingly slowly, They might trigger Creutzfeldt–Jakob disease: not just for cannibals, anymore. You might see agents that cause insanity, or sterility, or damn-foolishness (hmmmmm).

"Once CRISPR goes to war, you would see agents that cause germ-line genetic changes – nasty changes with built-in genetic drive that spread to the whole population."

I suppose we should add this to the debate about what to do about the new Caliphate. Peter Turchin has a series of articles on the same issue, applying his mathematical-history theory of 'cliodynamics'.

Perhaps understandably, Turchin is less keen on “ethnocide”.

As Turchin points out in the relevant article, world - and European - history is chock-full of examples of the kind of stuff Prof. Cochran playfully advocates. But the West doesn't seem to do that anymore, mostly because elite opinion has been captured by empathic compassion.  This almost-Buddhist ideology (bien-pensant liberalism to its enemies) is a natural fit to the rather weak government model of capitalist democracies, where it's important to keep all interest groups onside to ameliorate civil strife and get re-elected.

Government policy trundles along the vector sum of pressure group lobbying; the masses grudgingly acquiesce in the frequent stupidities which follow.

Until they don't.

Choose the best of your virtual children

I wrote critically of Nick Bostrom in my review of his "Superintelligence" book. But when he's not writing in a philosophical straightjacket, his intelligence and creativity produce rather better results, as here with Carl Shulman.

Suppose you have nine brothers/sisters. Your nine siblings will, of course vary in height, weight ... and intelligence. We know how to think about the relationship between the IQ of parents and their offspring (Steve Hsu explains here).

• We take the average of the parents' IQ, and that is the mean IQ of their children.


• The children do not of course have identical IQs, they're not clones; instead they populate the usual Gaussian distribution with standard deviation in the 7-11 IQ point range (rather than the usual population IQ SD of 15). The authors were conservative and used 7.5 in their simulation below.

So Carl and Nick have this table in their paper, from which you can see that the maximum IQ gap within ten children (dimmest to smartest) might be as much as 23 IQ points. Yes, I find that surprising too.

The table is based on a large scale simulation (10 million couples) and what I take it to be saying is this: if you use ten embryos and decide to implant the smartest, then you'll get an average 11.5 IQ point gain over just selecting a random embryo with no pre-screening for intelligence at all.

Is that important? It's the difference between a clerical and a professional job.

If you come from a large family, consider your siblings and consider whether any of this makes any sense.

We already do embryo selection for single-mutation diseases. A fertilised egg (in vitro) is allowed to divide until you have, say, an eight-cell clump - at this stage there is no functional differentiation. One cell is then extracted and its genome sequenced looking for the faulty gene. If the genome is fine, the seven remaining cells are implanted and the embryo grows to term with no ill effects; otherwise, discard and repeat. (It is more complex than this).

For IQ-based embryo selection to catch on we need a predictive model which can take a sequenced genome and predict with tight accuracy the resulting IQ (assuming decent nutrition, no abuse etc). We can't do this now as the relevant genes haven't yet been identified. But that should change within five to ten years. And we need to get the cost right down: doing 10 whole-genome sequences could be pricey.

Apart from the hassle of IVF and any legalistic hurdles, the way would then be open. What might be the consequences? Carl and Nick have a table - click on it to make it bigger.

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Just a note about IES on the right-hand side.

"The effectiveness of embryo selection would be vastly increased if multiple generations of selection could be compressed into less than a human maturation period. This could be enabled by advances in an important complementary technology: the derivation of viable sperm and eggs from human embryonic stem cells. Such stem cell derived gametes would enable iterated embryo selection (henceforth, IES):

1. Genotype and select a number of embryos that are higher in desired genetic characteristics;

2. Extract stem cells from those embryos and convert them to sperm and ova, maturing within 6 months or less;

3. Cross the new sperm and ova to produce embryos;

4. Repeat until large genetic changes have been accumulated."
...
"Using IES could deliver much more extreme results, and the fixed costs of using IES to produce enhanced embryos could be spread across large numbers of enhanced children. On the other hand, IES would compromise the typical genetic relationship between parents and children. To avoid negative effects of inbreeding, IES would require either a large starting supply of donors, or the expenditure of substantial selective power to reduce harmful recessive alleles. These factors would tend to push towards IES offspring being less genetically related to their parents (though more related to one another), and could reduce the appeal of IES."

All this and we haven't even mentioned genetic engineering, or CRISPR-Cas9.

I blogged that Toby Young had a piece about this back in September last year.

'The creatures outside looked from pig to man ...'

The good news:

"A gene-editing method could one day make pig organs suitable for use in people, scientists say. Prof George Church and colleagues used a technique called Crispr to alter the DNA of pig cells to create a better match for humans. The early work, in the journal Science, aims to address concerns about rejection and infection by viruses embedded in pig DNA. If successful, it could be an answer to the shortage of human donor organs."

The details:

"Crispr is a relatively new scientific tool that lets scientists snip and play around with the code of life - DNA. Prof Church, from Harvard University, used it to inactivate a retrovirus present in the pig cell line. This porcine endogenous retrovirus is potentially risky because it can infect human cells - at least in the lab. In tests on early pig embryos, Prof Church was able to eliminate all 62 copies of porcine endogenous retroviruses from the pig cells using Crispr. Next, he checked if the modified pig cells would still easily pass the retrovirus on to human cells. They did not, although there was still a small amount of transmission. Prof Church says the discovery holds great promise for using animal organs in people - what doctors call xenotransplantation."

... and the less good news:

"Years more research is needed before genetically modified pigs could be bred to grow organs for people."

Tough, of course, on the animals, but how many of us agonise on the subject of bacon?

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Subsequent my recent post (poor gym performance) I can confirm that today, Clare is snuffling like a cow-threatening badger while I'm nursing a sore throat and doing that limp man-thing.

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If they ever make "The Martian 2" do you think the star will be Jeremy Clarkson in a reasonably priced MAV together with a maddeningly-chirpy sidekick and a gormless, nerdy sparring partner?

The little people - the Draka solution

Did I mention that the Draka are a master race who have conquered half the world and subjugated everyone else as slave-serfs with the utmost cruelty?

Naturally the Draka have some plans for their always-dangerous subjects ... (from "The Domination": Book 3, The Stone Dogs, p. 632).

She paused. "Just out of curiosity, what's planned fo' the serfs along these lines?"

He relaxed. "Oh, much less. That was debated at the highest levels of authority, an' they decided to do very little beyond selectin' within the normal human range. Same sort of cleanup on things like hereditary diseases. Average the height about 50 millimeters lower than ours.

"No IQs below 90, which'll bring the average up to 110. No improvements or increase in lifespan so they'll be closer to the original norm than the Race. Some selection within the personality spectrum: toward gentle, emotional, nonaggressive types. About what you'd expect."

He laughed.

"An' a chromosome change, so that they're not interfertile with us any mo'; the boys can run rampant among the wenches as always without messin' up our plans."

"Yes," she said again, interest drifting elsewhere. "When can we do it?"

"Tomorrow would be fine, Tetrarch. The process of modifyin' the ova is mostly automatic. Viral an' enzymic, actually . . . Tomorrow at 1000 hours?"

Naturally a wench-serf will be the surrogate mother.

Homo Sapiens 2.0

It's been observed that the Germans would make a much better job at running Greece than the Greeks do. Some reactionaries have even been heard to observe that the British Empire made a better fist at governing its colonies (particularly in Africa) than the post-independence Governments.

At a technical level, these thoughts are certainly correct. They leave one factor out, however. The efficient Northern Europeans ran these countries in their own interests, not those of the indigenous populations. That's why the Greeks prefer their domestic leaders, incompetent and/or corrupt though they may be.

Genetics-aware commentators have been speculating for a while that we're on the verge of reprogramming our children with optimised alleles for health, athleticism, beauty, personality and intelligence. There's no technical reason why this shouldn't be reliable, safe, effective and possible in the next few decades. Sounds like the salvation of the human race - we can bootstrap ourselves to the next screen. Here's an update on work-in-progress.

But what of the parents and the broader community - do they think their own interests will align with those of their super-children? Hands up how many of you want to vote for your own extinction.

Every pre homo sapiens sub-species experienced this reality. The new guys are in the area and they're smarter and more competent than we are. We're gonna be toast. In the greater scheme of things, should we be happy about that or should we wipe out these upstarts while we can (if we can)?*

FWIW, my vote is in favour of letting the new guys have our space. But then, I always wanted humanity to get to the stars.

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* They say all Internet discussions eventually bring in the Nazis - this was precisely the argument National Socialists used against the Jews.