26 May 2022

From a sick body to a healthy one

The history of a failed head transplant

FirstVDS company blog, Habr

In 2015, the news thundered in the Russian media: Italian neurosurgeon Sergio Canavero is going to perform the world's first head transplant! His patient was supposed to be at that time 33-year-old programmer Valery Spiridonov, confined to a wheelchair due to spinal muscular atrophy.

Then doctors, physiologists and neurologists were outraged, then transhumanists and biohackers triumphed, then journalists fueled interest, then ordinary people were increasingly interested in the surgeon's extraordinary plans.

As we know, history has put everything in its place: the operation did not take place. But now there is an opportunity to calmly explain why it could not be carried out. Without thousands of dissatisfied and undocumented voices: "You don't understand! He can! A hundred years ago, they did not even dream of sewing a finger, so everything is possible in the near future!". Let us consider in more detail the prerequisites for such an operation, its complexity and existing technologies, as well as the vision of Canavero himself.

Why was a head transplant needed at all – or, scientifically speaking, cephalosomatic anastomosis (CSA)? In the case that Canavero promised to fulfill, the patient had a rare genetic disease that leads to gradual muscle degeneration and failure of internal organs. Indeed, CSA could be considered in this case as an "operation of despair", replacing the death programmed in fact with a kind of roulette – either death as a result of an unsuccessful operation, or life at least not worse in quality (Spiridonov's body was practically not functioning by the time they started talking about the operation). It is difficult to say how much such a transplant would be in demand in principle, but everything that develops medicine and technology and can help other patients in the future is an undoubted blessing.

And how much does it develop medicine? The association of the first level for the planned Canavero operation, in addition to the examples from fiction that were imposed in the teeth, were the experiments of the Soviet surgeon Vladimir Demikhov.


Vladimir Demikhov with not a two-headed, but a two-hearted dog Grishka

Everyone remembered about his half-forgotten transplants of heads to dogs in the USSR in the 1950s and 60s. Yes, Vladimir Petrovich worked out pioneering technologies, adopted and developed later for human organ transplantation all over the world. What makes a layman think: so, from an animal to a person, you need to take the proverbial one step? There is very little left, given the modern successes and technological equipment of medicine. But this is not the case. Demikhov did not go further in his experiments than stitching vessels and tissues, providing only uninterrupted access of oxygen to the brain and the survival of the central nervous system. It was the preservation of reflex and cognitive functions that he demonstrated in these experiments – the implanted donor heads moved and even tried to eat the usual food. But in the dry balance, this is just a functioning donor head.

In the case of CSA, it is necessary to solve a qualitatively different task – a donor head controlling the body. To have time to sew the main vessels, firmly fasten the vertebrae, connect the esophagus and trachea are time–consuming, but feasible tasks for conventional surgery. It is quite another matter to preserve the functions of peripheral nerves – motor, sensory.  Only in this case does the CSA make sense at all, and the goal justifies the means at least a little. After all, otherwise it is easier to replace the failing organs with hardware support of the function – like the same ventilator or artificial heart.

To restore control of the body, surgical techniques for suturing nerves and ways to help them in active and rapid regeneration are required. Do they exist today? Fundamentally– yes. Let's look at the medical literature. There is quite a clear algorithm of actions for surgery of damaged nerves in the extremities – an abbreviated quote:

There are four main stages of end—to-end reconstruction, which is the most commonly used nerve repair technique.

1) The ends of the nerves are prepared by surgically removing necrotic tissue, if necessary, the joint is bent or the bone is shortened;
2) The ends of the nerves are released for better mobility and tightened, leaving a minimum gap between them;
3) Ensure the correct connection of blood vessels and the correct positioning of the sutured ends of nerves along the axis of rotation;
4) The reconstructed nerve is stitched by suturing the epineurium, sometimes separate groups of nerve bundles are stitched. This is usually preferable for large nerves, where sensory and motor fibers can be isolated and stitched separately.


The general scheme of axon regeneration in case of damage (left) and various ways of stitching nerves and their individual bundles (right).

Possible complications and limitations are also discussed there. With such an operation, the main thing is the correct combination of the sheaths of the bundles of nerve fibers. The distal end of the axon (a segment on the side of the limb that does not contain a cell body) it will die, and new ones will have to regenerate in its place for the entire length. The regeneration of axons will go at a rather impressive rate of 1-3 mm per day. That is, roughly speaking, it is necessary to combine the "cable channels" correctly - and the individual "wires" will grow there on their own. And here we can only hope for the successful passage of the regenerating axon of the dissection site – not all of them will be able to overcome even a surgically stitched gap. And with incorrect positioning, of course, regeneration goes the wrong way, and the axons of motor neurons have an advantage in growth over sensory ones. All this can lead to organ denervation, incomplete motor function and local loss of sensitivity, even in the case of successful overall nerve regeneration.

And now information for reflection: bundles of motor neurons innervating the human biceps contain 774 axons.

And the total number of motor neurons whose axons pass through the spinal cord is about half a million! And it will not be a separate nerve "cord", clearly visible, topographically described and strictly corresponding to a particular function, which can be released, "clean the ends" and sewn. This is a wide tract of nervous tissue consisting of densely packed axons, on the slice of which motor neurons are located "somewhere in this area" (in the figure). How negative will the consequences be from the displacement of the ends of this "sausage" relative to each other, even by a tenth of a millimeter? How many axons of the donor head will not coincide with their projections on the new body – almost all of them?


Nerve processes passing through the spinal cord. The axons of sensitive neurons are afferent (the signal returns to the brain through them), indicated in blue. Axons of motor pathway neurons – efferent (the signal goes to the periphery along them) – are marked in red. The area of the red areas corresponds to about half a million motor neurons tightly packed into axon bundles.

Canavero had to answer these questions at the very beginning. He summarized the problem and its solutions in the form of the GEMINI project on spinal cord stitching.

The main "bells" in his speech are not the ambition of the project and the lack of technical details, but a bravura, even self-praising presentation. Canavero behaved like an outspoken showman, although he is a certified professional. But working for the public has done its job. Experts had strong skepticism, but the topic was picked up by the media and the public.

Two points are important to us from his speech: first, his statement about the unique properties of polyethylene glycol (PEG) to connect the ends of severed nerve bundles. Secondly, he focuses on the fact that motor neurons in the spinal cord have long processes (axons) that will regenerate slowly. But he claims the presence of a second, duplicate pathway, which is formed by often located neurons with short axons between them, which will regenerate much faster. Why are the only technical details actually the weak points of the project? Let's be skeptics.

In 1990, American scientists Krause and Bittner showed that the nerve recovers much better if its ends are connected using PEG. This substance effectively glues damaged cell membranes, and greatly increases the chance of repair. The work was done on worms, and did not go beyond the scope of a scientific experiment. The authors are particularly careful in discussing their results, saying that in mammals this process is much more complicated due to the smaller thickness of the axons, and requires "exceptional positioning accuracy of the connected ends." Kanavero, on the other hand, elevates this experimental method to the absolute, and he makes the processing of the connected ends of the spinal cord with PEG the cornerstone of the entire project. Nothing bad – just remember that convincingly showing the properties of PEG was one of Canavero's tasks.

But many biologists and doctors will disagree with the second loud statement. Our hero claims: there is an alternative motor pathway formed by frequently located neurons whose short axons will regenerate quickly. Well, let's analyze this statement.

Firstly, it is strange in itself that he quotes from the work of Leon Laruelle "La structure de la moelle épinière en coupes longitudinales" already in 1937. At that time, many modern methods like immunohistochemistry had not yet been discovered, even the DNA molecule was still unknown – such work was hopelessly old to be the only starting source. Secondly, it is now reliably known that the peripheral nervous system is formed either by long axons of neurons from the brain, or by two neurons connected through an intermediate ganglion. Yes, there are interneurons in the central nervous system – transmitting a signal from one neuron to another. But even hypothetically, such a system would be too slow for motor function due to the large number of synapses. It seems that Canavero specifically chose what to back up his ideas with – and found nothing more convincing than a monograph almost 3/4-century old.

Another strong, albeit indirect, argument against Canavero is a simple logical reasoning: if his method of splicing nerves with PEG scaled up to the spinal cord, then we would already be living in a different world today. No, not in the world of transplanted heads, but in the world of happy people who got out of a wheelchair after spinal injuries. No one has solved this problem so far, and thousands of people are irreversibly disabled as a result of injuries every year. If the use of PEG promised a real technology of nerve repair, since 1990 it would have already been developed into a revolutionary method of treatment, but surprisingly for a quarter of a century no one paid attention to it, except Canavero…

Isn't it a strange logic: to set a large-scale goal, where the most complex unsolved problem of medicine is stated simply as one of the tasks? It's like presenting a space station project where the energy source will be thermonuclear fusion – well, why, all the other details like the launch vehicle, spacesuits and living modules were developed before us, there is one task left - yes, difficult, but we can!

Let's check in the publications on the GEMINI project: could we? Since about 2016, Canavero has been collaborating with Asian surgeons Ren Xiaoping and Si-yun Kim. The first is the author of works on the transplantation of heads to mice, as well as on the "human model", that is, cadaveric material, as reported in the media.

The head transplant on the corpses took place, and could not have been particularly unsuccessful. No, just the same, it is possible to work out all surgical manipulations and techniques with CSA only in this way. And this work is probably the most qualitative and practically significant of all GEMINI. Detailed illustrations, specific techniques of fixation, stitching, and so on. But axons in a corpse, of course, will not regenerate, and only animal experiments are suitable for this. What successes has Xiaoping achieved on animals? To begin with, under the big words Head Transplantation in Mouse Model, there is a short article about sewing the head of one mouse onto another mouse, with the integration of the circulatory system and the preservation of vital signs (EEG) of the donor head. Here Ren Xiaoping simply reproduced on rodents the experiments of Demikhov and White half a century ago!

More interesting are the works of Si-yun Kim on rats. In one study, after cutting the spinal cord and applying PEG, it is claimed that rats moved their paws in response to electrical stimulation of vibrissae.


An illustration from an article by Ren Xiaoping. In response to irritation, the rat moves its hind limbs

Impressive, but... doesn't prove anything. You can cut, say, the entire car wiring harness, twist it at random again and connect it to the battery. If the brake lights light up at the same time, it does not mean that they are connected correctly, they just received an electrical signal, although it is unclear which way.

The GEMINI project review in the journal Surgery already talks about restoring the motor function of rats. The video attached to the review is the only proof of the results of the group's work. It shows both the operation of dissection of the spinal cord, and the course of healing. However, the application of PEG to the place of fusion of the spinal cord is not shown, and there is also no comparison of the mobility of all animals – there is only one barely crawling operated rat, as well as another (with ear marks, which are not on other frames) extremely emaciated rat at the end of the video. It is unclear what kind of animals we see, and what their behavior can be compared with. Another article Si-Yun Kim (sensitive people should not follow the link) is dedicated to the case of the recovery of one dog whose spinal cord was cut not entirely, but 90% "by eye". The dog was allegedly restored the ability to walk thanks to the use of PEG, but ... we do not have control animals for comparison.

Nevertheless, Canavero, in collaboration with Ren, in 2016, publishes a final article with the pretentious title "Houston, GEMINI landed" - rather inappropriate references to the US space program. He colorfully describes how he "gasped at the sight of recovered rats" from an article in Surgery by an Associated Press journalist, and successes with two mice sewn together, and about the prospects for the use of PEG. Deftly, like a magician sticking swords into a box with an assistant, Canavero created the illusion of a lot of work done, bypassing in fact all critical places. But if you look into his experiments hidden, like matryoshka dolls, using links in his GEMINI reviews, it becomes clear that he did not show anything important and new. Strictly speaking, for such a radical intervention as CSA, it has no sane performance statistics on animals, let alone preclinical studies. And this means that we unconditionally trust his articles as they are: for example, that only successful cases were not selected from all the experiments, there were no dogs and rats that PEG did not help, etc.

Further, as we know from recent history, strange things happened. Canavero seems to have announced that he would cooperate with Chinese surgeons and institutions, which means that Spiridonov does not suit him – they say it is unethical to transplant the head of a white man onto the body of an Asian. Spiridonov himself started a family and decided to devote time to it, and not to play dubious roulette with death. The bright and scandalous story quietly faded out, as befits any bench.

So, let's summarize. What Canavero proposed was a PR project based on his convinced statements that, as part of a head transplant, he would casually solve one of the most difficult neurosurgical tasks – the fusion of the spinal cord. Indicating the way to solve this problem, he actively created mythology, relying on separate, sometimes dubious studies – mosaic details that do not form any systematic approach by themselves.

By the way, what is Canavero doing now? And he, along with his old comrade Ren Xiaoping, switched to a new project – the spinal injuries mentioned in the article. He is going to transplant not the head, but only a section of the spinal cord to replace the damaged one. This, of course, already looks less like a PR project and is more close to reality, however, complete dissections of the spinal cord will then be required in two places, which doubles the risks for successful regeneration. In general, time goes by, plans and projects change, only the level of ownership of Canavero graphic editors remains unchanged:peresadka-golovy5.jpgLeft: from Canavero's presentation at TEDx in 2015; right – a drawing from his article from 2021

Is it worth publicly condemning vanity and accusing such science adventurers of hype? Probably not, so as not to stir up too much interest in their projects. But it is worth carefully analyzing from the point of view of specialists, and not in the form of discussions, but clearly indicating what they have said is real, and what is a lie and a substitution of concepts. After all, deliberately misleading about miraculous technology is a serious crime, at least against medical ethics.

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