Can You Transplant A Brain Into A Young New Body? And Would You?

Aging affects all of us and leads to cell and tissue loss of function, multiple diseases, and eventually death. And, even after decades of robust research and billions of dollars spent, there are only a few ways to slow it down and possibly reverse it with pharmacological means. Interestingly, the intervention testing program (IRP) run by the NIH showed that only a handful of drugs extend the lifespan of mice in any meaningful way. While the development of dual-purpose therapeutics to target aging and disease at the same time holds a lot of promise, the progress in this area is very slow, with the existence of less than a handful of credible companies with adequate resources and expertise.

One of the main areas that may lead to substantial advances in longevity and restoration of function is regenerative medicine. Rather than extending the lifespan of your old cells and organs, one can replace them with new ones. Hypothetically, in the future, even therapeutic cloning may be possible, where most of the body is replaced using "the clones without consciousness" or even generic bodies.

This concept has been avidly portrayed in many science fiction novels and movies, including the recent movie series "Altered Carbon". Most of the modern science fiction is focused on the concept of uploading the brain into a computer. The recent novel by Neal Stephenson, "Fall; or, Dodge in Hell" presents a wonderful concept of an alternative metaverse and there is a humorous sitcom “Upload” focusing on this on Amazon.

However, despite the pioneering efforts by Elon Musk's "Neuralink" Max Hodak's "Science Inc" and many other startups that followed, transferring the brain without losing individuality does not seem to be technologically possible in the foreseeable future. I spent some time working on brain-computer interfaces myself and have been granted patents in the area, but I decided to abandon the idea to focus on drug discovery technologies.

In this article, I will focus on several promising approaches for gradual brain replacement and, potentially, complete brain transplantation.

Replacing the Damaged Cells

Ever since the discovery of stem cells, scientists explored ways to "re-seed" the aging brain. Stem cells are undifferentiated cells that can transform into any type of cell of the body, like muscle or liver cells, cardiomyocytes, and even neurons. With each passing step of the differentiation process, they get more committed and take over new functions. The creation of the human body that happens in the uterus originates from stem cells, and in grown individuals we mostly find them in the bone marrow. During development, stem cells are either uni- or multi-potent, meaning they can either differentiate into one or multiple types of cells, respectively, mostly blood, immune, muscle, fat, skin, bone, and cartilage cells. However, theoretically and experimentally, through the exposure to specially design cocktails of growth factors they can be pushed into other directions. Since the urban legend says the number of neurons you get as one individual human being is finite, it would be quite amazing to use stem cells to differentiate into neurons or brain tissue, similar to what happens during the embryonic stage, right? But how?

Studies done on implementing stem cells onto the brain were done as early as 1917 by Elizabeth Hopkins Dunn, an incredible scientist from the University of Chicago, who was a pioneer in so many ways in her time. She managed to successfully transplant central nervous system tissue into adult mammal brains, observing the survival of the implemented neonatal cortex tissue. Even though others have tried to follow her lead, the unfortunate consensus at the time was that the brain is not capable of adaptation, so most stem cell approaches have stopped for a good sixty to seventy years.

Nowadays, stem cells are used to treat diseases like leukemia, multiple myeloma, and severe aplastic anemia, where the body is no longer able to synthesize new blood cells from bone marrow. In these scenarios, unhealthy cells are removed or destroyed by chemotherapy, and the person receives healthy stem cells isolated from the bone marrow, peripheral blood, or umbilical cord blood from a close donor, most likely with a family connection. This type of transplant is called an allogeneic transplant whereas when the patient receives stem cells from his own body this is called an autologous transplant. There are many risks involved, and the biggest one is rejecting the transplant, a process called Graft Versus Host Disease. When the types of HLA (human leukocyte antigen = proteins on top of the white blood cells) of both donor and patient don't match, the patient's immune system rejects and attacks the transplant. Even if the transplant isn't rejected, chemotherapy will probably cause severe side effects, like nausea and vomiting, muscle pain, inflammation, and various infections. Putting that on the side a bit, stem cell therapy is always changing for the better, and is already being experimentally used to treat breast cancer and juvenile chronic arthritis.

As stem cell therapy can be used to treat various types of cancer, it could potentially be used to treat other diseases of the body, especially tissues that can't repair themselves, like brain tissue. Stem cells that are to be used for possible brain regeneration originate from three different sources: from the inner cell mass of the embryo’s blastocyst, through cell reprogramming, or from different stages of brain development, such as adult or fetal brain stem cells. The possibilities to use neural stem cells as therapeutic vessels are endless. They can be genetically manipulated to target specific gene expressions of a diseased brain without affecting any other neurological process. They can also be obtained by playing with the protein nestin, which is expressed and synthesized in all precursor cells of the embryonic nervous system, but not in functionally committed neurons or glial cells. These cells can also be kept in culture for a long time and implanted in brains, when necessary, as was proven many times in experiments with laboratory test animals.

Such cells have already been used in preclinical studies to treat Parkinson's, Huntington's, and Machado-Joseph's diseases, and they showed great potential. Unfortunately, the mechanisms behind the treatments working are still not fully understood, even though early clinical results showed the integration of newly implanted stem cells into the tissue from the graft and triggered immunomodulation, which are both positive and promising observations. One of the possible advantageous mechanisms grafted cells can induce in the brain is releasing various growth factors that promote cell proliferation, migration, and differentiation. They can algo be beneficial by reducing neuroinflammation and promoting neuronal cell survival.

A big downfall of today's studies on brain stem cell therapy are comorbidities, that a lot of studies don't take into account. In fact, one of the common side effects that can change the outcomes of brain stem cell transplantation is aging, that often causes neuronal loss, impaired myelination, and decreased levels of neurotransmitters, which, in turn, can lead to decreased brain plasticity and neurogenesis. Studies performed on laboratory animals should also be repeated on aging conditions, since most of the stem cell therapy is intended for people that are suffering with age-related diseases.

There is also the risk of developing cancer, which is a common risk for all stem cell-based therapies. Stem cells might be induced to multiply uncontrollably, especially if they were pluripotent or had been subjected to long cell culturing periods (which may alter their epigenetic fingerprint). Furthermore, if viral vectors were used to reprogram these cells, they might trigger oncogenes and result in tumor formation. It is also risky to administer stem cells intravenously because they could easily aggregate forming emboli or travel to the lungs, spleen, or liver.

Stem cell transplantation should always be performed along with different therapeutic approaches, such as administering growth factors that induce stem cell mobilization and improve implantation or taking statins, which reduce oxidative stress in the brain and help with better transplant reception. All viruses and cells used in the stem cell manufacturing process require high quality reagents and rigorous genetic and safety testing. Stem cell therapy is a futuristic concept made accessible in the real world by the tremendous scientific effort made over the last decades. However, it is still considered an advanced therapeutic product, especially when it contains non-cellular components like scaffolds or matrices. Therefore, it requires extensive testing and regulations before being implanted in patients.

Still, neural stem cells are like blank canvases of life made by nature, and the possibilities they offer are humongous. For example, they could be used to grow organoids, tissues, and complete organs, at least in theory.

Brain Patches: Replacing Parts of the Brain

Another scientist I know, who is working on this topic is Jean Hebert. His research focuses on replacing parts of the brain with lab-grown brain organoids for CNS diseases. But some of the enabling technologies resulting from his research may be expanded in the future for more ambitious brain transplantation projects.

Brain or cerebral organoids are very specific neuronal cell cultures that were developed from human-induced pluripotent stem cell cultures, but with a slightly modified protocol. Grown spheroids of pluripotent stem cell cultures can be integrated within special solubilized membrane matrices which can support growing cells in a 3D environment, hence, producing organoids. Several scientific publications have already successfully shown that such cerebral organoid cultures present diverse populations of neurons and display processes like cortical development and cell migration. They also excrete their own extracellular matrix with many physiologically relevant components like hyaluronic acid, proteoglycans, and various functional enzymes.

Cerebral organoids are useful for numerous reasons, the first of them being the insight they offer into the developmental stages of the brain since they can grow from very simple structures to more complex ones. Further on, they can be used for drug screening given the fact they grow and multiply “fairly” quickly and simply. These properties make them great assets for drug screening to develop specialized drugs to cure several brain diseases. One of the most important uses of brain organoids is studying and simulating neuronal development and brain metabolism of several brain diseases, like Alzheimer's, Parkinson's, and Huntington's diseases. For example, cerebral organoids can be grown from skin cells taken from patients suffering from Alzheimer's disease and genetically engineered to become neuronal cells. Although mice models of Alzheimer's disease exist, they don't normally develop the full spectrum of the disease, thus, organoids are a much more accurate choice to study the early onset and physiology of the disease. Such organoid cultures can also be grown into the so-called “brain-on-a-chip” platforms, which are even easier to manage than organoids. These platforms contain multi-chamber tracking devices with seeded astrocytes and neurons co-cultures. Having these different types of cells in culture before growing them together in the same chamber allows scientists to track which genes may underly pathology and possible physiological changes in the disease models. Cerebral organoids can offer much more than experimental research. Indeed, they can also be used as transplants to replace and repair the damaged parts of a patient's brain.

Japanese scientist and stem cell innovator Yoshiki Sasai developed the first cerebral organoid in 2008, but it could not support itself because of the lack of vessel systems. However, this only started the ball rolling. Lately, the brain organoid approach has been used in a paper by Bao et al., where human embryonic stem cell-derived brain organoids have been implemented with needles into the damaged brain parts of cortical impact-modeled severe combined immunodeficient mice. Grafted organoids not only survived, but also differentiated, showed electroactivity, and extended long signal projections. Moreover, they promoted brain tissue repair and vascularization, learning and memory ability, and reduced glial scarring. The study also raised more questions, like how far the transplanted grafts can go in terms of repairing traumatic brain damage and scarring, as well as how to improve the survival of these neural stem cells in the brain in the future.

The studies on implementing neural stem cells into brains for the purpose of damage repair didn't stop there. A year later, Revah et al. from Stanford's University School of Medicine published a study in Nature in which they explain how they improved the ability of cerebral organoids to connect and integrate in vivo after they transplanted human stem cell-derived brain cortical organoids into the somatosensory cortex of newborn athymic rats. Organoids were fully grown from neural stem cells and injected into rat brains, essentially slightly pushing the actual brain a bit aside, as the authors explained. Organoids successfully grew, extended axons through the rat brain, and showed signal activation, with much more complexity than organoids only grown in in vitro systems. Human and rat cells connected in the auditory, motor and somatosensory cortices, as well as in subcortical regions including the striatum, thalamus and hippocampus, the latter being an area responsible for learning, memory formation, and consciousness. These studies offer the possibility of other neuronal cells being implanted into living brains, such as human microglia, human endothelial cells and GABAergic interneurons. All could be possibly used to study treatment for brain damage, the formation of brain connections, and disease etiology. Besides Alzheimer's and Parkinson's diseases, many more could be thoroughly studied, such as autism, epilepsy, and schizophrenia.

If we could transplant neuronal cells, brain tissue, and brain organoids into damaged or diseased brains, and if it worked, could we also do the same with whole brains or heads? The answer might be closer than we ever anticipated.

Head Transplantation - It May Be Closer to Reality Than You Think

The concept of head transplantation, technically termed cephalosomatic anastomosis, has rocked the media for many years. From the 1925's Alexander Belyaev's mad head transplant-performing scientist to Marvel's gorilla-bodied and human-headed Gorilla-Man, the idea of brain transplantation has always been provoking the human consciousness. It quickly expanded from the written word to the movie screen and resulted in popular cinematographic pieces like 1962's “The Brain That Wouldn't Die”, the newer 2008's “The X-Files: I Want to Believe”, or the newest one named “Altered Carbon”.

It didn't begin or stop on the big screen or in literature. Experimental head transplants started as early as 1908 when a French surgeon named Alexis Carrel and an American scientist named Charles Claude Guthrie grafted the head of one dog to another, despite it proved mostly unsuccessful. Dogs went through another round of experiments with a Soviet surgeon named Vladimir Demikhov, who transplanted a dog's head and the upper body onto another dog mostly to show how the blood supply connected, but the dogs managed to survive for almost a month. At this point, transplant rejections were a big problem that got solved by the development of immunosuppressive drugs and organ transplantation techniques in the mid-1900s. Another round of dog experiments was performed by Robert J. White in 1965 where he was grafting brain vascular systems of isolated dog brains onto existing dogs, but the animals did not survive for long. Later on, he also tried to connect blood vessels of opposing monkey heads onto each other, but even though it partially worked, there was a lot of blood clotting and immunosuppressive drug usage, and the animals did not survive. His experiments were widely criticized by the animal rights communities for being very violent and almost barbaric towards animals, and White was called “Dr. Butcher” or “Dr. Frankenstein”. This resulted in animal testing being stopped for a while, at least in the field of large mammal head transplantation.

However, since 2012, there have been some efforts regarding brain transplantation in mice models. Xiaoping Ren, a Chinese orthopedic surgeon, famous for being a part of the team that successfully performed the first hand transplant, tried to graft a mouse's head onto another mouse, and the grafted heads survived for about half a year. A bit later, he cut off the mice's heads, but left the brain stems connected, to see if he could connect the vascular systems and prove the bodies could be kept alive without life support. Somewhere around the same time, an Italian brain surgeon Sergio Canavero published the protocol that claimed it would make human head transplantation possible, which caused a lot of stir in the media and news outlets. Later on, Ren and Canavero published a review in which they discussed various protective strategies in head transplantation, as well as several protocols to keep the vascular systems connected and brains under hypothermia. Interestingly, they also suggested the usage of hydrogen sulfide as a neuroprotective agent and the use of blood substitutes.

In 2017, Ren and Canavero published work regarding a cross‐circulated bicephalic model of head transplantation to study the long-term effects of transplant rejection and blood flow restrictions during the head transference phase. By using vascular grafts, they connected the thoracic aorta and the superior vena cava from one rat to the carotid artery and extracorporeal veins of another rat. A third rat was used as a blood reservoir and its carotid artery and extracranial vein were connected to the donor rat with silicone tubes before the thoracotomy was performed on the donor rat. A pump and a heating device were connected to the silicone tubes to ensure regular blood supply and to prevent brain hypothermia. After performing the transplant surgery, the donor rat had pain and corneal reflexes, and the surgery opened up the possibility for the long-term survival of the patient. This represents one of the newest surgeries of this kind because it improves immensely the problem of restricted blood flow that all brain transplant surgeries had in the very beginnings of the field. Furthermore, since immunotherapy has been upgraded substantially in the past years, vascular grafting done to connect the blood vessels of the donor and the recipient during head transplantations might be just the thing that pushes this agenda into the future. Of course, more experiments are necessary, as always, but in 2017, Ren performed a successful, first-ever, head transplant surgery on a human cadaver.

According to them, the surgical steps of a head transplant are as follows:

1. One surgical team operates on the donor and the other one on the recipient. Both patients are fully monitored, and the recipient's head is kept under hypothermia. From the donor, only the spinal cord is kept under hypothermia, which lowers the kinetic rates of metabolic reactions and allows the surgeons to have more time for the operations without tissue decay.

2. Patients' necks are prepared for surgeries; the trachea, esophagus, and neck muscles are marked on each neck for later, and carotid and vertebral arteries are prepared. Laryngeal nerves are also cut and preserved for later.

3. The recipient's head is separated, flushed, and placed onto the donor's headless body. Both bodies are connected with tubes to preserve blood circulation until the surgery is over. Spinal cords are attached with polyethylene glycol glue, and the joined cord is secured by sutures. Polyethylene glycol can also be infused into the donor's blood circulation to promote better neuronal fusion.

4. The recipient and donor's vascular systems are connected through carotid and jugular silastic cannula. Any vessel that was used to connect the transplanted head to the donor's body is connected with sutures, all while the donor's circulation ensures blood flow through the recipient's head. All other structures of the neck and throat are reconnected to the donor's neck and stabilized. In the end, all muscles are connected, and the skin is sewn. When the surgery is done, the patient is brought to intensive care.

Such scientific procedures have always drawn a lot of media frenzy and raised many ethical dilemmas. The first feeling people get when they hear “head transplant” or “brain transplant” is simply an ick. Funnily enough, they don't seem to respond in the same way when they hear about liver or kidney transplants. It's possible that people connect emotionally more with brain or face transplants because they feel it's the part of the body that makes a person who they are, even though a person cannot function without kidneys either. We also don't know if the person will remain the same as they were before the transplant surgery, especially if their brain or head is just attached to another body and given the fact that the brain controls our memories, emotions, and reactions. Even some patients who went through heart transplants could recognize something changed about them after receiving another person's heart; maybe they started liking food or music they previously disliked. What's the situation with brain transplants, we don't exactly know. Another ethical concern here is the cost of the procedure itself. A surgery of that caliber cannot be anywhere near affordable for the average surgeon Joe, and it will most likely be accessible only to the rich. Along those lines, using a person's full body to perform the head transplant on it might deny the world a chance to use all the donated organs, and save only one life versus many.

Another huge, and rather tough, ethical question that comes to mind is – who should have the right to receive a human head/brain transplant first, and who should donate it? Some scientists agree the ideal recipient of a new human head should be a young and terminally ill person with no brain damage. The head of this person would be removed and attached to a body of a young brain-dead person whose body is otherwise functional and healthy. This person should also be a match for the recipient's immunotype and height. Surgeries on both patients would be done at the same time, with both bodies being kept under hypothermia and all while monitoring all the physiological functions.

So far, head transplant surgeries have not been successful on live animal models, let alone on humans. Sergio Canavero's protocol on head transplants and Ren's head transplant surgery on a human cadaver raised a lot of concerns and dilemmas among the editorial staff of the scientific publication American Journal of Bioethics (AJOB) – Neuroscience, especially the editor-in-chief and the professor of Bioethics at Emory, Paul Root Wolpe. Together with the Emory Neuroethics Program director Karen Rommelfanger, Wolpe argued that Canavero's team would be performing a very understudied and untested surgery that could risk the lives of its patients, all without having the necessary scientific background backed up by years of performing experimental procedures, safety testing, and quality control. Still, in the near future, someone will eventually perform the surgery on humans, and the ethical concerns will have to yield some guidelines.

While the ethical implications of such a procedure are immense, the technological limitations are such that it is too early to think about ethics. The largest technical limitation, like with any transplant, is still the immune response against the new “foreign” body. Even with increasing numbers and more frequent organ transplantations, particularly liver transplants, rejection still occurs very often, sometimes even a year after the surgery. The brain is also more specific and fragile in the sense of needing uninterrupted blood flow, to transport nutrients and oxygen in and out of the organ; damage can happen very quickly if normal blood flow is impaired. The most complex problem of them all regarding brain transplants is the proper attachment of brain nerves with corresponding spinal nerves and the preservation of the brain stem, which controls heart beating and breathing, two essential life functions. Severed axons would need to be properly mechanically aligned and that would require utmost precision during the procedure. Furthermore, postoperative care may prove even more complicated than the surgery itself, since the patient would have to go through immediate and intensive quadriplegia rehabilitation, possibly long-term breathing support, and bladder, vocal-cord, and communication therapy.

Old Brain Aging In the Young Body

Many of the recent initiatives in aging and longevity involve blood transfusion from young to old healthy subjects, stem cell therapies, and other regenerative medicine procedures. None of these approaches will yield a rejuvenative effect on the brain as placing it directly into a young body. Many of the theories for Alzheimer’s and other forms of dementia involve factors originating outside of the brain. So compared to many other alternatives, there is a higher chance of rejuvenation. Plus, the only one organ you need to think about with this strategy is the brain. It may be possible to gradually repair and replace the aging brain cells over time.

Will we be Able to Transplant our Brains into New Generic Bodies? And, if You Could Transplant Yourself into a New Body, Would You Do It?

While brain transplantation may be further from reality than head transplantation as there are many more technological barriers to overcome, and we do not yet know how to grow “unconscious clones” that are ready for therapeutic cloning but imagine for a second that you could do that.

When you perform thought experiments on this subject, the concept of a brain transplant into a clone or a head transplant seems very uncomfortable and weird. So I first asked one of my good friends who runs a venture fund focusing on age-associated diseases if he would ever consider transplanting his brain into the “tabula rasa” clone with no higher-order brain activity.

“You are kidding, right?”, he said. “In the case that this technology is available, why would I use a clone? Just look at me - I am a bold Jewish guy. I would rather be in a body of a 7-foot-tall Indian model guy with a six-pack and a twelve-inch reproductive organ”...

So I went a step further and conducted a Twitter poll. And while most of my followers are in longevity biotechnology, I expected most of the people to be disgusted and appalled by the idea. To my surprise, in 24 hours 796 people voted with 70% voting “Yes” and only 15% voting “No”. Indicating strong demand for this alternative.

To conclude, it is worthwhile noting that so far, despite multiple breakthroughs in enabling technologies, there are very few promising pharmacological interventions that may extend human lifespan and health span. It does seem like we are very far away from dramatic longevity interventions. Head transplantation and brain transplantation into the unconscious clones does not require us to have the fundamental understanding of the aging processes and may be a viable option for further investigation as most of the enabling technologies may already be available.