The Pig-Man Cometh?

This week, news broke regarding the successful transplant of a genetically modified pig heart into a human patient.

That’s right. A human being is currently alive, a 57-year-old human male, who has blood flowing through his veins that is being pumped by the heart of a pig.

If you’re like me, you may have two opposite reactions to this news. One reaction is a feeling of amazement at what science and doctors have been able to accomplish. The other reaction is something along the lines of creepiness, disgust, or perhaps downright horror.

When I was younger, I was greatly affected by an article by Joseph Bottum titled “The Pig-Man Cometh.” In it, he eloquently prophecies about and warns against the dangers of meddling with human and animal bioengineering. The article spooked me. It still spooks me. But these days… I’m a lot more conflicted. I’m no longer so sure that these sorts of experiments are wrong.

The Experiments

There is a long history of experimentation with cross-species transplantation, called xenotransplantation. This paper is quite a fascinating read. Blood transfusions from animals to humans have been used for centuries. In the 1800s skin grafts were attempted, as well as cornea transplants. Most of these failed. Then in the 1900s, with the benefit of rapidly advancing medical knowledge, all manner of experiments were attempted. Some were successful. During the 1960s a number of chimpanzee kidney transplants were attempted, with one patient living for 6 months. In 1984, a baboon heart was transplanted into an infant, who lived for several weeks. Insulin derived from pigs was used for a time to treat diabetes. The list goes on and on.

The problem with most of these experiments is that the organ is rejected by the recipient’s immune system. So in this latest transplant, the pig heart was genetically modified in order to decrease the changes of the organ being rejected:

In the heart implanted in Bennett, three genes previously linked with organ rejection were “knocked out” of the donor pig, and six human genes linked with immune acceptance were inserted into the pig genome.
Researchers also deleted a pig gene to prevent excessive growth of the pig heart tissue.

I find it astounding and inspirational that our knowledge of bioengineering and has progressed enough to let us make these sorts of changes. We are learning the programming language of nature itself! But questions lurk… where does it stop? Where do we draw the line? Do we even want to draw a line, and are we capable of enforcing one?

What does it mean to be human?

Do you stop being human if you have a prosthetic limb? Clearly not. You’re still you. What if you had a mechanical heart? During surgeries, machines routinely perform the job of circulating blood while the heart is operated upon. An artificial heart. Do you stop being human while you have a machine-heart? No. You’re still a human being even while undergoing heart surgery.

Do you stop being human if you have the heart of a pig? No… you’re still human, but something inside us may be creeped out by the idea. It seems almost wrong somehow. The heart is such a vital organ, such an intimate part of you. Yet people have heart transplants from other humans all the time, and nowadays we don’t think much of it. What difference does it make whether the heart is a machine, from another human, or… from a pig?

I would argue that it doesn’t make any difference, and our sense of unease is not rational. The individual components are not what makes someone human. After all, our bodies are composed of literally trillions of cells, bacteria, and viruses, all working together in concert to create something greater. Rather, it is the gestalt, the sum of the components, the pattern, which makes us human.

What about a robot with artificial intelligence which perfectly mimics a human? One which displays emotion, cries, laughs, reacts, thinks, ponders, explores, creates. Would this be human? If not, why not? Does flesh and blood make a human a human? Or is it perhaps our souls? Something nebulous, intangible, deep down inside us at a spiritual level which make us truly special?

The world is not black and white

When I was younger, I viewed the world much more concretely. I had a religious belief system which provided a foundation for my thoughts and how I interpreted the world. There was good and evil, moral actions and immoral actions, angels and demons, humans and animals, all categorized into their own boxes that did not mix. But as I learned more about the world, I came to realize… life is not black and white. Life is full of messiness, of blurred lines, of squiggles instead of straight edges. It is not discrete separate buckets but rather a continuum. This is true at every level you look at, from the weirdness of quantum mechanics, to the fierce debates over social issues, to the messy explosions of stars going supernova. If life really were easily categorizable, we would have a complete picture by now.

All living things are connected. I don’t mean that in the whole Lion King circle of life way, although that is certainly true. What I mean is that, according to the scientific theory of evolution, all living things are literally connected because they share a common ancestor. Our closest living relatives are chimpanzees. Pigs are a close relative as well, because they are mammals like humans.

When I was religious, I believed that humans were somehow separate from animals. God made us specially and separate, with a soul. We had an eternal destiny in heaven or hell after we died, while animals simply ceased to exist after death. If you have this perspective, it makes sense that blurring the line between human and pig might be a bad thing. We would be attempting to play God, meddling in the Way Things Were Supposed To Be.

But when I discovered that evolution was true, the lines between human and animal were no longer clear. Humans ARE animals! Certainly we are unique and special animals, but animals nonetheless. And more and more, we are discovering that we are not quite as unique as we thought. Does tool use make us human? Other animals use tools. Animals make music. Animals make art. What about language? Dolphins and elephants have forms of communication that many consider to be a primitive language, and don’t forget Koko the gorilla. What about our sense of empathy, or our cooperation? Other animals have that too. The ability to consider the future, or remember past events, and plan accordingly? Research suggests animals can perform this as well! What makes us “human”, I suppose, is that we do these things better and more proficiently. It is more a matter of degree than of complete categorical difference.

Uplift

People are fascinated by the idea of talking animals. Depictions of intelligent animals which can speak are everywhere, from Aesop’s Fables to Peppa Pig. Growing up, I loved the Chronicles of Narnia, where talking animals like Aslan the lion or Reepicheep the mouse are major characters. As an adult, I have come to love science fiction. It is a wonderful genre which expands our imagination, explores who we are, and makes us think about what may be possible.

One fascinating series I enjoy is called the Uplift Saga, by David Brin. Set a couple hundred years in the future, the premise is that humans have bioengineered several Earth species to have human-level intelligence. This process is called uplift. Uplifted dolphins, chimpanzees and gorillas are considered people. They can speak, have civil rights, and even work together as crew members on spaceships.

How cool is that! What fascinating perspectives could an intelligent animal share? What hopes and dreams, songs and poems and abilities could they contribute? Why should homo sapiens be forever the only fully intelligent animals on Earth? Perhaps our burgeoning knowledge of bioengineering is the mechanism by which life on Earth begins to evolve consciously instead of blindly.

Losing our humanity?

I don’t think transplanting a genetically modified pig heart into a human is a bad thing. But what about the experiments of the future? What about uplifting other animals, or uplifting ourselves? I believe the crux of Bottum’s concern in his essay is this:

…what difference does it make whether the researchers’ intention is to create subhumans or superhumans? Either they want to make a race of slaves, or they want to make a race of masters. And either way, it means the end of our humanity.

The worry that new technology will create a divide between the haves and the have-nots is an old one. But time has shown that although new technology does create temporary disparities, those disparities disappear as the technology grows to scale and becomes widely adopted. At first only the elite might have access to swords, or guns, or televisions or the internet (or genetically enhanced babies). But soon, even the poorest gain access to these innovations. What household in America doesn’t have a TV or internet? Nearly none. First for the few, then for the many… that is simply how progress works. That is not creating a race of masters. It is lifting the boat for all. Therefore I dismiss that aspect of his concerns.

As for losing our humanity, as I explained earlier, I don’t believe there is a sharp, distinct line between humans and animals. We do not lose our humanity by transplanting a pig heart. We do not lose our humanity by engineering babies to be free of genetic diseases, or to be stronger or more intelligent. We in fact would eliminate much suffering, extend lives and increase health, just as proper nutrition and medicine help us thrive. We could even conceivably increase our innate sense of empathy and kindness. Perhaps in the future, the descendents of humans will bear little similarity to us. We would be to them as neanderthals are to us. However I don’t see that as losing our humanity, but rather as enhancing it.

This is not to say that there aren’t things which are clearly right or wrong at the extremes. Raising creatures with human-level awareness for the sole purpose of being organ donors is scary and dystopian. Let’s not do that. But though there isn’t a sharply defined line between us, pigs don’t have human-level awareness. They don’t have the same breadth of mental perceptions and faculties that people do. Plus, humans eat all manner of animals, just as animals eat other animals. Life eats life, that is the way of nature. Does that make it okay? Or should we all become vegan and cease all experimentation? I’m conflicted on this issue. But I do know that saving people is good. Preventing human suffering and allowing people to live who would otherwise die is a noble goal. My opinion for now is that we should minimize animal suffering as much as possible while still doing the experiments needed to achieve these goals.

An alternative

There is actually a fascinating alternatives to animal experimentation which is also being researched and pursued… lab-grown organs! Using 3D printing, human cells are seeded onto a plastic base and provided nutrients until they grow into a living, functioning organ. So far, the only successful transplant into a human has been a bladder. But even that is amazing. Small sections of 3D printed tissue, such as skin or lung tissue, are being used in cosmetic and pharmaceutical testing. This has been reducing the need for animal trials. If we can perfect these techniques, it would solve the need for both human and animal transplants and the ethical grey areas that go with them. There is a long way to go, so pursuing animal transplant research as well makes sense. But lab-grown organs seem extremely promising, and I think most of our resources should be poured into this alternative as it is both practical and more moral.

The future

I believe life is an ever-unfolding adventure and mystery. We are on a collective journey of discovery about ourselves, our fellow living creatures, and the wonderful, beautiful, terrible, vast universe around us. I do not see bioengineering as something to be avoided. It is a tool, which like all tools can be used for good or bad.

Some believe that humanity is on a moral decline. I tend to believe the opposite. Though we still have vast moral problems, when we compare ourselves to a couple centuries ago, the differences are startling. Slavery was commonplace, women were second-class citizens, gay people could be executed by law, and concerns about the environment or animals were nearly nonexistent. We have made tremendous strides in our collective sense of morality. Though I am no longer religious, I still believe in God, and I believe all is unfolding as it should. Let us not fear the future or the marvels it holds. But let us also tread carefully and wisely.

Ivermectin: Are Both Sides Wrong?

Ivermectin isn’t in the news much compared to a few months back, but I have friends and family who are still talking about it. I recently came across a fascinating analysis of the situation from psychiatrist and blogger Scott Alexander. He formerly wrote at slatestarcodex.com and currently continues his efforts at astralcodexten.substack.com. Razor sharp and prolific, he is funny, incredibly detailed, and ferociously dedicated to rationality and examining all sides of an issue.

His post is titled “Ivermectin: Much More Than You Wanted To Know” and it is aptly named… the post is extremely long and detailed. I haven’t read the entire thing, as a lot is an analysis of various studies, and I skimmed through those sections. However in the second half, Scott presents an elegant and fascinating hypothesis. First though, let’s go through some background on scientific studies, then look at Scott’s steps and reasoning.

Studies and Metastudies

It’s easy to find a study that proves just about anything. Eggs are bad for you. Eggs are fine! Ditch the butter… actually wait bring it back. Caffeine, chocolate, and meat might be simultaneously bad, good, and somewhere in between. How can we make sense of all this?

The answer is we have to look at meta-analyses. These are statistical examinations of a group of studies, to try to find a signal within the noise of the varying conflicting individual studies. Unfortunately, this process is not simple or cut-and-dry. New techniques are practices for meta-analyses are still being developed. Additionally there are a lot of ways that bias, error, and fraud can creep into studies, which can throw off the meta-analyses. So a systematic review of the studies is needed to check for things such as p-hacking, publication bias, faked data, and more. It takes hard work to root out all the various issues.

Analyzing the Ivermectin Studies

Thankfully, Scott has done the heavy lifting for us. He starts with a list of 29 studies, 25 of which appear to show that Ivermectin beats a placebo using various measures such as hospitalization rate, viral load, deaths, etc. This list is from ivmmeta.com, a site doing a meta analysis of ivermectin studies. The green boxes are studies where ivermectin did better than the placebo, the red boxes are where it did worse:

At first glance, this seems pretty convincing. However, all studies are not made equal. It is very possible that the results of a given study ought to be discounted because of fraud, bad methodology, insufficient sample sizes, etc. Here comes the mind-numbing, tedious bit. Scott goes through each study, and, for various reasons which you can read about if you really want, narrows downs the credible studies to these:

About halfway through his analysis, Scott learned of the efforts of epidemiologist Gideon Meyerowitz-Katz, who was doing a similar review of ivermectin studies. They ended up with similar but not identical lists. For his final list of credible studies, Scott eliminated any study that either he or Gideon found questionable. Which narrows it down to these 11 studies:

Scott summarizes the work thus far (note, I think his count is off by 1 for some reason):

We’ve gone from 29 studies to 11, getting rid of 18 along the way. For the record, we eliminated 2/19 for fraud, 1/19 for severe preregistration violations, 10 for methodological problems, and 6 because Meyerowitz-Katz was suspicious of them.

…but honestly this table still looks pretty good for ivermectin, doesn’t it? Still lots of big green boxes.

However, there are 3 studies showing ivermectin performed worse than a placebo. Additionally, there is some question as to which performance measures are the best statistic to use in the graph:

Meyerowitz-Katz accuses ivmmeta of cherry-picking what statistic to use for their forest plot. That is, if a study measures ten outcomes, they sometimes take the most pro-ivermectin outcome. Ivmmeta.com counters that they used a consistent and reasonable (if complicated) process for choosing their outcome of focus…

So, Scott decided to select what he considered the most relevant, common-sense outcome variables from these 11 studies, then performed some statistical analysis. Depending on how he ran the analysis he found a trend in favor of ivermectin, but not enough to be statistically significant. Or, a statistically significant trend in favor of ivermectin, but only when not following best practices. There aren’t enough of the credible studies remaining to draw a firm statistical inference.

Still though, it does seem like something is going on. We don’t necessarily want to discount these studies simply because the proof isn’t statistically iron-clad. And so finally, we reach the fascinating hypothesis.

Worms!

The most powerful studies in favor of ivermectin for treating COVID-19 come from areas of the world that have lots of worms. In the list of credible studies, the one by Mahmud took place in Bangladesh. The study by Ravakirti was from East India. The study by Bukhari was from Pakistan. Etc etc. These are all places with lots of various types of parasitic worms. Here is a chart of the prevalence of roundworms (source):

Why would studies from these areas show that ivermectin improves COVID-19 outcomes? One explanatory mechanism is that the helminth worm can produce changes in the body’s microbiome. These changes modulate how the immune system responds, suppressing it, which decreases the body’s ability to fight the worm… as well as COVID-19. So, how to stop the helminth worms from messing with your immune system during a COVID-19 infection? Kill them with ivermectin.

Another explanatory mechanism is related to a common treatment for COVID-19: corticosteroids. Much of the damage from COVID-19 comes from the body overreacting to the virus (remember cytokine storms?) Thus, doctors use corticosteroids to decrease the body’s immune response, protecting it from the harmful overreactions. However, these immune responses are also necessary for the body to control a roundworm called Strongyloides stercoralis. Without a properly functioning immune system, the worms multiply out of control in a “Strongyloides hyperinfection” (yikes!) and the patient often dies. How to use corticosteroids without suffering a worm hyperinfection? Kill them with ivermectin.

The good ivermectin trials in areas with low Strongyloides prevalence, like Vallejos in Argentina, are mostly negative. The good ivermectin trials in areas with high Strongyloides prevalence, like Mahmud in Bangladesh, are mostly positive.

Amazingly, it may all come down to: ivermectin does help with COVID-19, but only in areas that also have issues with worms. And this would make both sides of the debate… wrong. Scott cautions that this is of course just a possibility. There are a lot of (educated) judgement calls going into his analysis, and it is just one of multiple meta-analyses. But I hold Scott in high regard, and it would do a lot to explain the confusing results of the studies. It’s possible ivermectin does have some very small benefit in areas without worms. But it definitely isn’t some sort of wonder drug for COVID-19 as many proponents claim.

Takeaways

Science is really hard. The whole process is riddled with the potential for human bias, mistakes, and fraud. Many of the studies showing miraculous results for ivermectin were later shown to be fraudulent… check out the section on the study by Cadegiani for a good laugh, or perhaps a good cry. The scientific community is continuing to improve upon methodological and statistical processes as well as ways of detecting problems with studies, but it takes time for researchers and journals to uniformly adopt them.

Some studies showing that ivermectin helped were probably right… but only for people who were dealing with parasitic worms! For your average American, ivermectin probably won’t do squat. You can take it if you really, really want (it is fairly safe, though there are potential side effects), but you’re likely wasting your time and money.

Those who shout down and mock proponents of ivermectin by shouting “HORSE DEWORMER!!!” and accuse them of being anti-science are not being helpful. People are concerned and scared, and they are trying to follow the science of these pro ivermectin studies. Such mockery only adds fuel to the fire of tribalism and increases our divide. Instead, I believe we should have a calm discussion of these highly complicated issues, and continue to educate people on the scientific process.

On the flip side, those who blindly believe in every new fad treatment for COVID based on a few studies are being equally unhelpful. Their fixation on these fringe treatments often stems from a reflexive anti-establishment attitude (The FDA says don’t take it? Screw them, I’m gonna take it!) as well as anti-vaccine sentiments. I understand the impulse to be skeptical of the medical establishment, and at times that skepticism can be valid. But it is also important to be skeptical of your own skepticism, and to realize that more often than not the experts know what they are talking about.