June 29, 2013

Technical hurdles have been overcome for the first human head transplant

The project for the first head transplant in man is code-named HEAVEN/GEMINI (Head Anastomosis Venture with Cord Fusion.

UPDATE - Welcome Reddit readers. This article made the front page of reddit. Thanks for the upvotes.

UPDATE - I cover the internet and news reactions to this article and added technical information.

UPDATE I consider this proposed procedure in the context of organ donation and xenotransplantation.

The technical hurdles have now been cleared thanks to cell engineering. As described in his paper, the keystone to successful spinal cord linkage is the possibility to fuse the severed axons in the cord by exploiting the power of membrane fusogens/sealants. Agents exist that can reconstitute the membranes of a cut axon and animal data have accrued since 1999 that restoration of axonal function is possible. One such molecule is poly-ethylene glycol (PEG), a widely used molecule with many applications from industrial manufacturing to medicine, including as an excipient in many pharmaceutical products. Another is chitosan, a polysaccharide used in medicine and other fields.

HEAVEN capitalizes on a minimally traumatic cut of the spinal cord using an ultra-sharp blade (very different from what occurs in the setting of clinical spinal cord injury, where gross, extensive damage and scarring is observed) followed within minutes by chemofusion (GEMINI). The surgery is performed under conditions of deep hypothermia for maximal protection of the neural tissue. Moreover, and equally important, the motoneuronal pools contained in the cord grey matter remain largely untouched and can be engaged by spinal cord stimulation, a technique that has recently shown itself capable of restoring at least some motor control in spinal injured subjects.

Surgical Neurological International - HEAVEN: The head anastomosis venture Project outline for the first human head transplantation with spinal linkage (GEMINI)

* a head of a monkey was transplanted in the 1970s but the spinal cord could not be repaired at the time
* Spinal cords have been regrown in rats.
* In 2000, guinea pigs had spinal cords surgically cut and then protected with PEG chemical (like what is proposed here) and they had over 90% of spinal nerve transmission restored with a lot of mobility and function restored

Over the last 30 years, scientists have worked to chemically encourage regrowth. Two chemicals, chondroitinase and FGF, show strong signs of doing exactly that--in rats, at least. Independently, over the past three decades, each chemical has shown some promise in restoring simple but crucial rat motor processes, like breathing, even with entirely severed spinal cords.

Two surgeons in the field figured that a combination of the chemicals might enhance the regrowth even more. The surgeons, from Case Western Reserve University and the Cleveland Clinic, began by entirely severing the spinal cords of 15 rats to ensure no independent, natural regrowth. That shut off the rats' bladder control (a nervous system process that is especially important in rats, since they urinate often and to mark their territory). The researchers then injected the two growth-stimulating chemicals into both sides of the severance, and reinforced the gap in the cord with steel wiring and surgical thread.

The Cleveland clinic has the full description of the rat spinal cord repair.

The indications for HEAVEN would be far-reaching (including non-brain cancer), but, given the dearth of donors, a select group of gravely ill individuals would be the target. This would include for instance people with some kinds of muscular dystrophies, which prove eventually lethal and a source of major suffering.

A Possible Head Transplant Scenario is Described

What follows is a possible scenario in order to give the reader a feel for the whole endeavor.

Donor is a brain dead patient, matched for height and build, immunotype and screened for absence of active systemic and brain disorders. If timing allows, an autotransfusion protocol with D's blood can be enacted for reinfusion after anastomosis.

The procedure is conducted in a specially designed operating suite that would be large enough to accommodate equipment for two surgeries conducted simultaneously by two separate surgical teams.

The anesthesiological management and preparation is outlined elsewhere. Both R and D are intubated and ventilated through a tracheotomy. Heads are locked in rigid pin fixation. Leads for electrocardiography (ECG), EEG (e.g., Neurotrac), transcranial measurement of oxygen saturation and external defibrillation pads are placed. Temperature probes are positioned in tympanum, nasopharynx, bladder, and rectum. A radial artery cannula is inserted for hemodynamic monitoring. R's head, neck, and one groin are prepped and draped if ACHP is elected. A 25G temperature probe may be positioned into R's brain (deep in the white matter), but, as highlighted, a TM thermistor should do.

Antibiotic coverage is provided throughout the procedure and thereafter as needed.

Before PH, barbiturate or propofol loading is carried out in R to obtain burst suppression pattern. Once cooling begins, the infusion is kept constant. On arrest, the infusion is discontinued in R, and started in D. An infusion of lidocaine is also started, given the neuroprotective potential. Organ explantation in R is possible by a third surgical team.

R's head is subjected to PH (ca 10°C), while D's body will only receive spinal hypothermia; this does not alter body temperature. This also avoids any ischemic damage to D's major organs. R lies supine during induction of PH, then is placed in the standard neurosurgical sitting position, whereas D is kept upright throughout. The sitting position facilitates the surgical maneuvers of the two surgical teams. In particular, a custom-made turning stand acting as a crane is used for shifting R's head onto D's neck. R's head, previously fixed in a Mayfield three-pin fixation ring, will literally hang from the stand during transference, joined by long Velcro straps. The suspending apparatus will allow surgeons to reconnect the head in comfort.

The two teams, working in concert, would make deep incisions around each patient's neck, carefully separating all the anatomical structures (at C5/6 level forward below the cricoid) to expose the carotid and vertebral arteries, jugular veins and spine. All muscles in both R and D would be color-coded with markers to facilitate later linkage. Besides the axial incisions, three other cuts are envisioned, both for later spinal stabilization and access to the carotids, trachea and esophagus (R's thyroid gland is left in situ): Two along the anterior margin of the sternocleidomastoids plus one standard midline cervical incision.

Under the operating microscope, the cords in both subjects are clean-cut simultaneously as the last step before separation. Some slack must be allowed for, thus allowing further severance in order to fashion a strain-free fusion and side-step the natural retraction of the two segments away from the transection plane. White matter is particularly resistant to many of the factors associated with secondary injury processes in the central nervous system (CNS) such as oxygen and glucose deprivation and this is a safeguard to local manipulation.

Once R's head is separated, it is transferred onto D's body to the tubes that would connect it to D's circulation, whose head had been removed. The two cord stumps are accosted, length-adjusted and fused within 1-2 minutes: The proximal and distal cord segments must not be accosted too tightly to avoid further damage and not too loose to stop fusion. A chitosan-PEG glue, as described, will effect the fusion. Simultaneously, PEG or a derivative is infused into D's blood-stream over 15′-30′. A few loose sutures are applied around the joined cord, threading the arachnoid, in order to reinforce the link. A second IV injection of PEG or derivative may be administered within 4-6 hours of the initial injection.

The bony separation can be achieved transsomatically (i.e., C5 or C6 bodies are cut in two) or through the intervertebral spaces. In both R and D, after appropriate laminectomies, a durotomy, both on the axial and posterior sagittal planes, would follow, exposing the cords. In D, the cord only has been previously cooled. If need be, pressure in D is maintained with volume expansion and appropriate drugs.

The vascular anastomosis for the cephalosomatic preparation is easily accomplished by employing bicarotid-carotid and bijugular-jugular silastic loop cannulae. Subsequently, the vessel tubes would be removed one by one, and the surgeons would sew the arteries and veins of the transplanted head together with those of the new body. Importantly, during head transference, the main vessels are tip-clamped to avoid air embolism and a later no-reflow phenomenon in small vessels. Upon linkage, D's flow will immediately start to rewarm R's head. The previously exposed vertebral arteries will also be reconstructed.

The dura is sewn in a watertight fashion. Stabilization would follow the principles employed for teardrop fractures, anterior followed by posterior stabilization with a mix of wires/cables, lateral mass screws and rods, clamps and so forth, depending on cadaveric rehearsals.

Trachea, esophagus, the vagi, and the phrenic nerves are reconnected, these latter with a similar approach to the cord. All muscles are joined appropriately using the markers. The skin is sewn by plastic surgeons for maximal cosmetic results.

R is then brought to the intensive care unit (ICU) where he/she will be kept sedated for 3 days, with a cervical collar in place. Appropriate physiotherapy will be instituted during follow-up until maximal recovery is achieved.

More Background and History of head transplants and spinal cord repairs

There have been many studies on spinal cord repair, but many have the repair performed after waiting for one week. It would be far easier to repair if the repair is done right away and separation and reattachment is done in a careful surgical way.

In 2000, there was immediate recovery from spinal cord injury through molecular repair of nerve membranes with polyethylene glycol. (10 pages) Immediate and full (over 90%) recovery from a severed spinal cord was performed in adult guinea pigs with the application of one of the chemicals proposed in the human head transplant project.

A brief application of the hydrophilic polymer polyethylene glycol (PEG) swiftly repairs nerve membrane damage associated with severe spinal cord injury in adult guinea pigs. A 2 min application of PEG to a standardized compression injury to the cord immediately reversed the loss of nerve impulse conduction through the injury in all treated animals while nerve impulse conduction remained absent in all sham-treated guinea pigs. Physiological recovery was associated with a significant recovery of a quantifiable spinal cord dependent behavior in only PEG-treated animals. The application of PEG could be delayed for approximately 8 h without adversely affecting physiological and behavioral recovery which continued to improve for up to 1 month after PEG treatment.

Stem cell injections help repair damage and restore function.

The early-stage neural stem cells grew new axonal connections across the injury and re-established significant mobility, something that hasn't been done before, Tuszynski said. Both rat and human neural stem cell transplants restored function.

The stem cells improved mobility on a 21-point scale, from 1.5 after spinal cords were severed to 7 after the treatment. The rats were treated a week after the injury, a "clinically relevant" model for human therapy.

Rats with spinal cord injuries and severe paralysis are now walking (and running) thanks to researchers at EPFL. Published in the June 1, 2012 issue of Science, the results show that a severed section of the spinal cord can make a comeback when its own innate intelligence and regenerative capacity is awakened.

In 1959, China announced that it had succeeded in transplanting the head of one dog to the body of another twice.

On March 14, 1970, a group of scientists from Case Western Reserve University School of Medicine in Cleveland, Ohio, led by Robert J. White, a neurosurgeon and a professor of neurological surgery who was inspired by the work of Vladimir Demikhov, performed a highly controversial operation to transplant the head of one monkey onto another's body. The procedure was a success to some extent, with the animal being able to smell, taste, hear, and see the world around it. The operation involved cauterizing arteries and veins carefully while the head was being severed to prevent hypovolemia. Because the nerves were left entirely intact, connecting the brain to a blood supply kept it chemically alive. The animal survived for some time after the operation, even at times attempting to bite some of the staff.

Other head transplants were also conducted recently in Japan in rats. Unlike the head transplants performed by Dr. White, however, these head transplants involved grafting one rat's head onto the body of another rat that kept its head. Thus, the rat ended up with two heads. The scientists said that the key to successful head transplants was to use low temperatures.

* Effective repair of traumatically injured spinal cord by nanoscale block copolymer micelles (Nature Nanotechnology, 2009) These experiments treated the damage after about ten minutes and were able to get a lot of movement back in most cases. The damage was a crushing of the spinal cord, so the transplant procedure would have better results because it would be a careful separation of the spinal cord under cold conditions with immediate application of the protectant chemicals.

Spinal cord injury results in immediate disruption of neuronal membranes, followed by extensive secondary
neurodegenerative processes. A key approach for repairing injured spinal cord is to seal the damaged membranes at an early stage. Here, we show that axonal membranes injured by compression can be effectively repaired using self-assembled monomethoxy poly(ethylene glycol)-poly(D,L-lactic acid) di-block copolymer micelles. Injured spinal tissue incubated with micelles (60 nm diameter) showed rapid restoration of compound action potential and reduced calcium influx into axons for micelle concentrations much lower than the concentrations of polyethylene glycol, a known sealing agent for early-stage spinal cord injury. Intravenously injected micelles effectively recovered locomotor function and reduced the volume and inflammatory response of the lesion in injured rats, without any adverse effects. Our results show that copolymer micelles can interrupt the spread of primary spinal cord injury damage with minimal toxicity.

Improvement in the locomotor function in the micelle-treated group was evident by a more rapid increase of BBB scores in the first 14 days and continuation of improvement over the following two weeks. Specifically, at 28 days post-injury, the BBB scores were 12.5 + or minus 3.1. From a clinical perspective, an animal with a BBB score equal to or less than 11 lacks hindlimb and forelimb coordination, whereas a score of 12 to 13 corresponds to occasional to frequent forelimb and hindlimb coordination. Reaching a BBB score of 12 is significant in that it is a sign of axonal transduction through the lesion site

Illustration of the monkey head transplant from the 1970s.

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