Xiaoping Ren

Head Transplantation in Mouse Model

The mouse model of allo‐head and body reconstruction (AHBR) has recently been established to further the clinical development of this strategy for patients who are suffering from mortal bodily trauma or disease, yet whose mind remains healthy. Animal model studies are indispensable for developing such novel surgical practices. The goal of this work was to establish head transplant mouse model, then the next step through the feasible biological model to investigate immune rejection and brain function in next step, thereby promoting the goal of translation of AHBR to the clinic in the future.

Allogeneic head and body reconstruction: mouse model.

There is still no effective way to save a surviving healthy mind when there is critical organ failure in the body. The next frontier in CTA is allo‐head and body reconstruction (AHBR), and just as animal models were key in the development of CTA, they will be crucial in establishing the procedures of AHBR for clinical translation.

Houston, GEMINI has landed: Spinal cord fusion achieved

In June 2013, the world was taken by storm by the announcement that a full head (or body) transplant was possible.[1] This key achievement would have been made possible by the GEMINI spinal cord fusion protocol.

Human head transplantation. Where do we stand and a call to arms

Ever since being announced in 2013, the HEAVEN head transplant initiative – also known as allogeneic head body reconstruction, the GEMINI spinal cord fusion protocol and the first head transplant procedures in mice[1,2,3,5,6,7,8] have received scathing remarks from several official medical, surgical, and ethical bodies.[3] Medical history shows us that many of the “quantum leaps” almost always fly in the face of conventional wisdom. Todays standard of care was yesterdays experimental treatment, and before that, in many cases, it was one mans visionary idea. The history of medicine includes many examples of ideas that were initially ridiculed or rejected by the medical establishment but that later became widely adopted, thanks to the courage of researchers and clinicians who stood by their ideas, often in the face of withering criticism from their colleagues. Notable examples would include Semmelweiss (antiseptic handwashing), Gruentzig (balloon angioplasty), Rous (viruses and cancer), Marshall (Helicobacter pylori and ulcer), Prusiner (prions), Pasteur (germs), Mendel (heredity), and many others. The last in the list is HEAVEN. The question arises spontaneously: Why? Why so much acrimony for a lifesaving procedure? The reason is psychological: HEAVEN opens the Pandoras box of medical failures. “Despite biomedical research blossoming in terms of accumulated data, evolving technologies, and published articles… few advances in biomedical science materialize into human applications that affect health; even when successful, the translation sometimes takes decades… as proposed discoveries accumulate, a major challenge is how to promptly translate them into something useful. The current pipeline remains inefficient… effective application in saving lives and improving health has been limited. The excuse that not enough time has passed is not really satisfactory… human genetics research has received tremendous funding… few lives have been saved because of accumulated human genetics knowledge to date, and future prospects (e.g., extension to personalized and precision medicine) also are not promising… intellectual fascination in neuroscience for many decades has led to few new practical applications. It is unclear whether newly announced efforts in this… discipline will fare any better… even the most recent ones, e.g., optogenetics are already a decade old… most Nobel prizes in medicine have been given recently for discoveries that offer brilliant mechanistic insights, but have not yet moved (and may never substantially move) the dial of life expectancy.”[4] This is the state of affairs in biomedicine in the early 21st century. Medicine at large has failed for chronic conditions or is still stuck with gross procedures (injecting insulin for diabetes - since 1922). The only bright spot – infectious diseases – is losing its sheen, as resistance is mounting around the world to available antibiotics. Acute care medicine - which is often lifesaving - is equally often trailed by long-term disability. And of course, bioengineering advances cannot be conflated with biochemical medicine. Had “brilliant mechanistic insights”[4] proven “brilliant,” we would be free – or on the way to – of the major killers that affect humankind. There would be no need for a full body exchange. HEAVEN bears brutal testimony to this simple fact. When you have to change a body because you cannot fix it, that is a sign of failure. Actually, the whole field of transplantology attests to the fact that our biochemical insights have led nowhere, despite vast amounts of money spent over the past 50 years! Since we cannot reverse a biological process gone awry, we are left with little else than replacing this or that organ. Unfortunately, humility is not a part of the medical lore. No one in the media and society at large truly grasped this fact: HEAVEN stands for failure. Whose fault is it? There are several parties at fault, and it would be too long a list, but standing at the very top is the current peer review system that vets research to be published: “A major advance may be difficult to express in primary ‘original’ articles reviewed by other similar-thinking specialists. The ability to break loose from the shackles of narrowly focused specialists who thwart out-of-the-box ideas may characterize major disruptive innovation.”[4] Had it been for the specialists of the time, no airplane would be flying over our heads presently, since heavier-than-air flying vehicles were deemed impossible in 1900. Moreover, many other current technologies equally apply (a medical favorite: Mullis’ polymerase chain reaction). So what is the solution? Involving private entrepreneurs is one,[4] since “they have strong reasons to generate truly working solutions and effective interventions rather than simply publish articles and obtain grants.” Is it so? Founded in 2012, Breakthrough Prizes are the richest prizes in science, bankrolled by Silicon Valley billionaires, including Googles Sergey Brin, Facebooks Mark Zuckerberg, 23 and Mes Anne Wojcicki, Alibabas Jack Ma, and DST Global Milner. This years prizes were awarded for optogenetics research and an assortment of genetic mutations that have not changed the prognosis of the related conditions an iota (https://www.newscientist.com/article/dn28461-glitziest-science-prize-hands- out-21m-to-1300-top-researchers). This means that the billionaires still rely on the traditional peer review process. And that is a setback to properly financing breakthrough science. This is not surprising. As the world knows, in June 2015, the two authors delivered their combined talks to the AANOS/ICS annual meeting in Annapolis, Maryland. Unfortunately, the science behind spinal cord fusion and other aspects of head transplantation were basically unknown to the audience and - one can safely conclude - to the cadres of critics (and reviewers), despite seven papers published in both SNI[1,2,3] and Central Nervous System Neuroscience and Therapeutics.[5,6,7,8] Even Dr. Whites work has been grossly misconstrued: Ethical criticisms were both unsupported and populist. Happily, on August 27, 2015, Xinhua, Chinas official news agency announced the start of the cooperation between the two authors toward the first human head transplantation. A plan has been laid down that involves experimentation with brain-dead organ donors. The manufacturing of the GEMINotome, an ultra-sharp nanometer-grade blade and of a negative pressure micro connector for polyethylene glycol circulation, is a part of this endeavor. In the meantime, scientists from the Institute of Theoretical and Experimental Physics in Moscow (Prof. Maevsky and Orlova) have volunteered their know-how to boost the HEAVEN neuroprotection protocol. Health professionals from all around the world, including the USA, have offered to be a part of the transplant team. Thus, it is most unnerving that no patients’ association ever contacted any of us, likely advised against by “academic critics,” the same kind of “experts” billionaires rely upon.[9] Hence, we thank this journal and its editor in allowing us to make its readership apprised of this simple fact: that academic arrogance once again is stifling scientific innovation. We urge all those interested, and above all those who stand to benefit the most, the patients, to look at the facts and start funding for our project. At the same time, all unbiased physicians who would want to independently test several aspects of this paradigm are urged to contact us. HEAVEN is growing into a major international collaboration. In the meantime, people are dying because we doctors failed. This is a time for humility. But also, a time to act. Doctors, patients, and funding bodies (including well-meaning but naive billionaires), together.

Polyethylene glycol-induced motor recovery after total spinal transection in rats

Despite more than a century of research, spinal paralysis remains untreatable via biological means. A new understanding of spinal cord physiology and the introduction of membrane fusogens have provided new hope that a biological cure may soon become available. However, proof is needed from adequately powered animal studies.

The Cardioprotective Effects of Late-Phase Remote Preconditioning of Trauma Depends on Neurogenic Pathways and the Activation of PKC and NF-κB (But Not iNOS) in Mice

Background: A superficial abdominal surgical incision elicits cardioprotection against cardiac ischemia–reperfusion (I/R) injury in mice. This process, called remote preconditioning of trauma (RPCT), has both an early and a late phase. Previous investigations have demonstrated that early RPCT reduces cardiac infarct size by 80% to 85%. We evaluated the cardioprotective and molecular mechanisms of late-phase RPCT in a murine I/R injury model. Methods: Wild-type mice, bradykinin (BK) 2 receptor knockout mice, 3M transgenic mice (nuclear factor κB [NF-κb] repressor inhibitor of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha [IκBα(S32A, S36A, Y42F)]), and inducible nitric oxide synthase (iNOS) knockout mice were analyzed using a previously established I/R injury model. A noninvasive abdominal surgical incision was made 24 hours prior to I/R injury and the infarct size was determined at 24 hours post-I/R injury. Results: The results indicated that a strong cardioprotective effect occurred during late-phase RPCT (58.42% ± 1.89% sham vs 29.41% ± 4.00% late RPCT, mean area of the infarct divided by the mean area of the risk region; P ≤ .05; n = 10). Furthermore, pharmacological intervention revealed the involvement of neurogenic signaling in the beneficial effects of late RPCT via sensory and sympathetic thoracic nerves. Pharmacological experiments in transgenic mice-implicated BK receptors, β-adrenergic receptors, protein kinase C, and NF-κB but not iNOS signaling in the cardioprotective effects of late RPCT. Conclusion: Late RPCT significantly decreased myocardial infarct size via neurogenic transmission and various other signaling pathways. This protective mechanism differentiates late and early RPCT. This study describes a new cardiac I/R injury prevention method and refines the concept of RPCT.

The Age of Head Transplants.

If we disregard religious myths, the first reference to a body swap is found in the work of Pu Song Ling, a Chinese poet who died in 1715 but only became famous later on when his collection Strange Tales from a Chinese Studio was published. In one tale, a demon, Judge Lu, after some vicissitudes, falls in with Mr Zhu and humors his request of giving his wife, who “is not at all a bad figure, but she is very ugly,” a new face, actually the head of a nice-looking young girl. What happened is that:

First cephalosomatic anastomosis in a human model

Background: Cephalosomatic anastomosis (CSA) has never been attempted before in man as the transected spinal cords of the body donor and body recipient could not be “fused” back together. Recent advances made this possible. Here, we report on the surgical steps necessary to reconnect a head to a body at the cervical level. Methods: Full rehearsal of a CSA on two recently deceased human cadavers was performed at Harbin Medical University, Harbin, China. Results: The surgery took 18 hours to complete within the time frame planned for this surgery. Several advances resulted from this rehearsal, including optimization of the surgical steps, sparing of the main nerves (phrenics, recurrent laryngeal nerves), and assessment of vertebral stabilization. Conclusion: Several specialties are involved in a full-scale CSA, including neck surgery, vascular surgery, orthopedic surgery, plastic surgery, gastrointestinal surgery, and neurosurgery, as well as the operating staff. This rehearsal confirmed the surgical feasibility of a human CSA and further validated the surgical plan. Education and coordination of all the operating teams and coordination of the operative staff was achieved in preparation for the live human CSA.

Restoration of motor function after operative reconstruction of the acutely transected spinal cord in the canine model

Background: Cephalosomatic anastomosis or what has been called a “head transplantation” requires full reconnection of the respective transected ends of the spinal cords. The GEMINI spinal cord fusion protocol has been developed for this reason. Here, we report the first randomized, controlled study of the GEMINI protocol in large animals. Methods: We conducted a randomized, controlled study of a complete transection of the spinal cord at the level of T10 in dogs at Harbin Medical University, Harbin, China. These dogs were followed for up to 8 weeks postoperatively by assessments of recovery of motor function, somato‐sensory evoked potentials, and diffusion tensor imaging using magnetic resonance imaging. Results: A total of 12 dogs were subjected to operative exposure of the dorsal aspect of the spinal cord after laminectomy and longitudinal durotomy followed by a very sharp, controlled, full‐thickness, complete transection of the spinal cord at T10. The fusogen, polyethylene glycol, was applied topically to the site of the spinal cord transection in 7 of 12 dogs; 0.9% NaCl saline was applied to the site of transection in the remaining 5 control dogs. Dogs were selected randomly to receive polyethylene glycol or saline. All polyethylene glycol‐treated dogs reacquired a substantial amount of motor function versus none in controls over these first 2 months as assessed on the 20‐point (0–19), canine, Basso‐Beattie‐Bresnahan rating scale (P < .006). Somatosensory evoked potentials confirmed restoration of electrical conduction cranially across the site of spinal cord transection which improved over time. Diffusion tensor imaging, a magnetic resonance permutation that assesses the integrity of nerve fibers and cells, showed restitution of the transected spinal cord with polyethylene glycol treatment (at‐injury level difference: P < .02). Conclusion: A sharply and fully transected spinal cord at the level of T10 can be reconstructed with restoration of many aspects of electrical continuity in large animals following the GEMINI spinal cord fusion protocol, with objective evidence of motor recovery and of electrical continuity across the site of transection, opening the way to the first cephalosomatic anastomosis. (Surgery 2017;160:XXX‐XXX.)

A cross-circulated bicephalic model of head transplantation

A successful cephalosomatic anastomosis (“head transplant”) requires, among others, the ability to control long‐term immune rejection and avoidance of ischemic events during the head transference phase. We developed a bicephalic model of head transplantation to study these aspects.