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Surgical Neurology International
Editorial
OPEN ACCESS
For entire Editorial Board visit :
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Editor:
James I. Ausman,
MD, PhD
University of California, Los
Angeles, CA, USA
The “Gemini” spinal cord fusion protocol: Reloaded
Sergio Canavero
Turin Advanced Neuromodulation Group (TANG), Turin, Italy
E‑mail: *Sergio Canavero ‑ sercan@inwind.it
*Corresponding author
Received: 04 November 14
Accepted: 17 November 14
Published: 03 February 15
This article may be cited as:
Canavero S. The "Gemini" spinal cord fusion protocol: Reloaded. Surg Neurol Int 2015;6:18.
Available FREE in open access from: http://www.surgicalneurologyint.com/text.asp?2015/6/1/18/150674
Copyright: © 2015 Canavero S. This is an open‑access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Sir,
Cephalosomatic anastomosis (CSA), that is, the surgical
transference of a healthy head on a surgically beheaded
body under deep hypothermic conditions, as conceived
by Robert White,
[39]
hinges on the reconnection of the
severed stumps of two heterologous spinal cords (reviewed
in reference).
[7]
On the occasion of the first CSA between primates in
1970, Dr White hewed to the view that a severed spinal
cord could not be reconnected, thus leaving the animal
paralyzed.
[7,39]
In 1902, Stewart and Harte reported on CN, aged
26 years, who had her spinal cord severed by a
0.32 caliber
gunshot. The distance between the segments of the cord
was 0.75 inch, as verified by all five attending physicians:
“The
ends of the cord were then approximated with
3 chromicized catgut sutures passed by means of a
small staphylorraphy needle, one suture being passed
anteroposteriorly through the entire thickness of the cord
and the other two being passed transversely. This part
of the operation was attended with unusual difficulties
because of…the wide interval between the fragments, the
catgut frequently tearing out before the ends were finally
brought together.”
Sixteen months later, “the
patient slides
out of bed into her chair by her own efforts and is able
to stand with either hand on the back of a chair, thus
supporting much of the weight of the body.”
[36]
Importantly, they reviewed several cases of patients with
sharp wounds to the cord that spontaneously recovered
from initial paraplegia. Their conclusion was that “the
operation of myelorrhaphy will be specially indicated in
cases in which the cord has been cut by a sharp instrument
or severed by a projectile.”
[36]
Whereas myelorrhaphy
was not effective at 15 months in a young paraplegic
patient after a self‑inflicted
0.38 caliber
gunshot,
[16,35]
nonetheless, a huge body of evidence accrued over
the past decades made the first part of Stewart and
Harte’s prediction highly relevant.
[33]
In fact, had White
attempted to reattach the sharply severed cord stumps in
the monkey, the possibility exists that the animal might
have recovered at least partial motricity.
In this paper, I will detail the recently proposed GEMINI
spinal cord fusion (SCF) protocol in view of the first
human CSA,
[7]
giving new meaning to Stewart and
Harte’s prediction. The recent study by Estrada
et al.,
[14]
in which rats whose spinal cords were sharply transected
recovered ambulation, confirms that CSA (HEAVEN: 7)
is feasible.
Two key principles underlie the GEMINI SCF:
•
A sharp severance of the cords is not as damaging as
clinical spinal cord injury
•
The gray matter “motor highway” is more important
than the pyramidal tract in human motor processing.
PRINCIPLE 1: SHARP SEVERANCE
The key to SCF is a sharp severance of the cords themselves,
with its attendant minimal damage to both the axons in
the white matter
and
the neurons in the gray laminae.
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This is a key point: A typical force generated by creating
a sharp transection is
less than 10 N
versus approximately
26000 N
experienced during spinal cord injury, a
2600× difference!
[33]
A specially fashioned diamond microtomic snare‑blade
is one option (unpublished); a nanoknife made of a thin
layer of silicon nitride with a nanometer sharp cutting
edge is another alternative.
[8,9]
Notably, the mechanical
strength of silicon is superior to that of steel.
[34]
PRINCIPLE 2: GRAY MATTER “MOTOR
HIGHWAY” VS PYRAMIDAL TRACT
In man, motricity is only modestly subserved by long
axonal systems coursing through the spinal white
matter as taught in contemporary anatomical and
neurology textbooks (parenthetically, “Subdivision
of
the (human) white matter…into tracts is…not feasible,
because most of the tracts mix with one another and
overlap”).
[27]
Skilled voluntary movements of the hand
in man are often considered to be dependent on the
direct access of motor neurons (MN) from the primary
motor cortex to the cord (monosynaptic Pyramidal
Tract). However, indirect pathways from the motor
cortex (e.g. corticobulbospinal pathways via, e.g., the
reticulospinal tracts) and
spinal interneuronal systems
by far contribute the majority of inputs to the MNs: In
man, the corticospinal tract predominantly terminates
in the intermediate layers of the spinal cord where
many interneurons are located.
[1]
Laruelle
[24]
wrote:
L’association plurisegmentaire est réalisée, non seulement
par les voies cordonales connues, mais par un système de
fibres intrinsèques de la substance grise, pouvait parcourir
plusieurs segments successifs: Elles confèrent une fonction
conductrice à la substance grise de la moelle
(The
plurisegmentary association is brought about not only via
the known cordonal pathways, but via a gray‑matter‑based
system of intrinsic fibers, which cover up to several cord
segments: These confer conductive properties to the
cord gray matter)”.
This association is further enacted
via short fibers lying closest to the spinal gray matter
that connect nearby spinal segments over short or very
short distances (e.g., the lateral limiting layer of the
Ground Bundles).
[26]
This explains why «in
man, recovery
of motor function including the distal movement is
compatible with …degeneration of 83% of the pyramidal
tract fibers»,
[20]
as occurs for lesions restricted to the
human lateral corticospinal tracts.
[28]
In the words of
Bucy
et al.,
[6]
“The
pyramidal tract…is not essential to
useful control of the skeletal musculature…In the absence
of the corticospinal fibers other fiber systems, particularly
some…multineuronal mechanism passing through the
mesencephalic tegmentum, are capable of producing
useful, well‑coordinated, strong and delicate movements
of the extremities.”
In a recent case report, a subject with tetraplegia
(ASIA A) recovered 15 months later to ASIA D, despite
a 62% atrophy of the white matter tissue at the injury
epicenter,
[12]
including the pyramidal tracts. Even in
multiple sclerosis, long regarded as the prototypical
white matter (long axons) disease,
it is the damage to
the gray matter that accounts for most of the related
motor disability – even in cases without white matter
loss!
[30]
Similar anatomical arguments – propriospinal
transmission versus spinothalamic tract in the case of
nociception – could be made for the sensory return.
[18]
In GEMINI, the gray matter neuropil will be restored by
spontaneous regrowth of the severed axons/dendrites over
very short distances at the point of contact between the
apposed cords.
FUSOGEN‑ASSISTED
NEURAL RECONSTITUTION
GEMINI exploits special substances (fusogens/sealants:
Poly‑ethylene glycol [PEG], Chitosan) that have the
power to literally fuse together severed axons or seal
injured leaky neurons.
[7,11,29]
It is based on the concept
of
biological fusion,
which occurs both naturally (e.g., in
myoblasts) and artificially (e.g. hybridoma cells): Up
to 10% of severed axons in some invertebrates can
undergo spontaneous fusion with their separate distal
segments.
[10]
Different technologies can induce axonal
fusion: Chemical, laser, and electrofusion.
[10,34,40]
Chemical
fusion is likely mediated by a dehydration effect and
volume‑exclusion aggregation of membrane lipids
bringing adjacent lipids into physical contact.
[11]
Two
scenarios are particularly attractive: (i) A PEG containing
solution is flowed for 2 min (more than 3’ is actually
deleterious) over the lesion site, and then flushed out, as
outlined by Bittner
et al.;
[5]
or (ii) a semi‑interpenetrating
network of PEG and photo‑cross‑linkable chitosan can be
employed as an
in situ‑forming
nerve adhesive/fusogen.
[2]
Chitosan nanoparticles or PEG can also be injected IV for
several hours to enhance the effect.
[7]
Interestingly, there
may be a body temperature effect on PEG’s viscosity and
efficacy (Kouhzaei
et al.).
[21]
In contrast, chitosan in an
injectable solution that moves throughout the systemic
circulation – apparently regardless of viscosity: Thus
the route of administration does not appear to matter
in a manner similar to PEG.
[11]
Animal experiments on
transected cords have already given proof‑of‑principle of
the feasibility of fusogen‑assisted SCF.
[7,11,21,22,32]
Anyway,
PEG‑mediated functional reconnection between closely
apposed proximal and distal segments of severed axons
takes many minutes of absolute immobility of the axon
segments and an untested period of immobilization of
the tissue for the repair to become permanent.
[11]
The
question is whether this is actually required for successful
reconstitution of motor (and sensory) transmission, also
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considering how perfect one‑on‑one axonal alignment is
impossible. As proven by Bittner
et al.
[5,31]
in peripheral
nerves
in vivo,
behavioral recovery is excellent and
improves over time after PEG fusion. This means that
a
sufficient number of axonal proximal stumps get fused with
the distal counterparts in such a way to ensure appropriate
electrophysio‑logical conduction, likely the result of tight
axonal packing. This number is likely low (10–15%), and yet
enough for recovery, reflecting the potential for substantial
plasticity in the injured CNS.
[34]
A similar figure applies to
the damaged spinal cord in man,
[4]
where the number of
axons in the spinal white matter is estimated at over 20
million, with about 1 million pyramidal fibers. Also,
reconnection with an adjacent axon, as long as it is not
an extreme mismatch, may restore acceptable function.
[34]
Dense axonal packing would ensure that a number of
fibers would get fused.
Notice that during CSA no gap is expected between
the cord stumps. Should have this not been the case,
transplantable miniature neurono‑axonal constructs
internalized within engineered tubes could have been
used to fill the gap (e.g.
[13]
). Actually, PEG appears to be
more than sufficient even in this context. Estrada
et al.
[14]
have fully transected rats’ spinal cords and filled the gap
with PEG 600: They reported massive elongation of
axons from all fiber populations (including interneurons)
that grew into the PEG bridge and became remyelinated
upon entering the CNS tissue. The axon growth effect
was already visible at 1 week posttreatment, grew in
time steadily and was long‑lasting. Rats could recover
physiologic locomotion.
Tangentially, collagen conduits containing autologous
platelet‑rich plasma have allowed successful axonal
regeneration and neurological recovery in
clinical
peripheral nerve injury with gaps up to 12 cm (16 cm
along with an added sensory nerve graft).
[23]
neural processing, and pattern generating networks caudal
to a spinal cord lesion lose an adequate, sustainable state
of excitability to be fully operational: SCS (15–60 Hz,
5–9 V) provides a multi‑segmental tonic neural drive to
these circuitries and “tune” their physiological state to a
more functional level.
[25]
Thus, “loss
of voluntary control of
movement may be attributed to not only a physical disruption
of descending connections, but also to a physiological
alteration of the central state of excitability of the spinal
circuitry…(spinal cord) stimulation may facilitate excitation
of propriospinal neurons which support propagation of the
voluntary command to the lumbosacral spinal cord…after
repetitive epidural stimulation and training…multiple, novel
neuronal pathways and synapses (are established).”
[3]
The
result is recovery of intentional movement in the setting
of complete paralysis of the legs.
[3,25]
Similar arguments
and results apply to the cervical spinal cord.
[37]
Of course,
useful plasticity will not only occur in the cord, but also at
higher levels, including the motor cortex.
[12,19]
CONCLUSION
In sum, the GEMINI SCF protocol hinges on the
following steps [Figure 1]:
•
The sharp severance of the cervical cords (donor’s and
recipient’s), with its attendant minimal tissue damage
•
The exploitation of the gray matter internuncial
sensori‑motor “highway” rebridged by sprouting
connections between the two reapposed cord stumps.
This could also explain the partial motor recovery
a
b
ELECTRICITY‑ACCELERATED RECOVERY
In GEMINI, local sprouting between neurons in the
gray matter (see above) will reestablish a functional
bridge over days to weeks. This process is accelerated
by electrical stimulation via application of a spinal cord
stimulator (SCS) straddling the fusion point. For instance,
1 h of continuous electrical stimulation at 20 Hz applied
right after suturing together the stumps of a transected
peripheral nerve cut the regeneration time from 8–10 to
3 weeks; similar accelerations are seen in man.
[17]
The role of electrical stimulation goes well beyond
acceleration of axonal and dendritic regrowth. The spinal
cord has the capacity to execute complex stereotyped
motor tasks in response to rather unspecific stimuli even
after chronic separation from supraspinal structures.
However, being deprived of sufficient supraspinal drive,
Figure 1: (a) Longitudinal cut along a primate spinal cord depicting
the internuncial system (gray
matter motor highway)
and the nano‑
size of the proposed severance (left). The red circle on the right
side of this panel is the pyramidal tract, shown in two exploded
views of a sharply transected cord (middle right) and of the cord
in the vertebral canal (lower middle right). (b)Visualization of the
severed pyramidal tract. The uppermost image depicts a motor
neuron in the cortex sending forth the axonal prolongation. Middle
panel:The pyramidal tract (red) and a portion of its severed axons.
Lower panel:The sharply severed axonal extensions (adapted from
Laruelle 1937 and several images in the public domain)
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•
•
in a paraplegic patient submitted to implantation
of olfactory ensheathing glia and peripheral nerve
bridges: A 2‑mm bridge of remaining cord matter
might have allowed gray matter axons to reconnect
the two ends
[38]
The bridging as per point 2 above is accelerated by
electrical SCS straddling the fusion point
The application of “fusogens/sealants”: Sealants
“seal” the thin layer of injured cells in the gray
matter, both neuronal, glial and vascular, with little
expected scarring; simultaneously they fuse a certain
number of axons in the white matter.
13.
14.
15.
16.
17.
During CSA, microsutures (mini‑myelorrhaphy) will
be applied along the outer rim of the apposed stumps.
A cephalosomatic anastomosee will thus be kept in
induced coma for 3–4 weeks following CSA to give time
to the stumps to refuse (and avoid movements of the
neck) and will then undergo appropriate rehabilitation in
the months following the procedure.
In addition, the immunosuppressant regime that will be
instituted after CSA is expected to be pro‑regenerative.
[15]
18.
19.
20.
21.
22.
ACKNOWLEDGMENT
The author wishes to thank the thousands of scientists and
patients from around the world who benefited him with their
encouragement and suggestions.
23.
24.
25.
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Surgical Neurology International
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http://www.surgicalneurologyint.com/content/6/1/18
NOTE:
The interested reader is referred to the author’s
39.
40.
TEDx talk for further details on HEAVEN/GEMINI:
http://www.ustream.tv/recorded/52890140 (minutes 32–50),
and to the author's book: Head Transplantation And The
Quest For Immortality (CS/ AMAZON 2014).

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