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McMaster scientists regenerate spinal cord - Revolutionary new technique uses intestinal cells

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  • #16

    what an astute observation! When Harry Goldsmith first started doing omentum transplants to the spinal cord, many of us in the scientific community were fascinated by the possibility of intestinal omental cells and growth factors interacting with the spinal cord. The omentum is an incredible structure. It is one of the most active vascular tissues in the body. The omentum vascularizes the guts and carries virtually all the nutrients that we ingest. Within 24 hours after a pedicled omentum graft is placed on the spinal cord, the omentum is sending blood vessels into the spinal cord, along presumably with its attendant cells and growth factors. The gut is constantly renewing itself and the omentum likewise has to respond rapidly to changes of the gut. There is an important story here but unfortunately it has not been well-investigated and remains outside of the mainstream of the spinal cord injury field. I was fascinated by Dr. Kao's adoption of the omentum graft as a means of preventing scar formation after the surgery. This is quite an interesting and innovative idea and one that is worthy of attention by the scientific and clinical community.


    [This message was edited by Wise Young on August 18, 2001 at 08:40 AM.]


    • #17
      Another article about the research being done at McMaster U

      Canadian researchers have been able to rebuild nerves in rats by injecting the spinal cord with cells from the intestine

      Tom Arnold
      National Post
      A Canadian laboratory has discovered that nerves can regenerate in the spine when cells from the intestine are transplanted into a severed spinal cord.

      The McMaster University finding is being touted as a major breakthrough in spinal-cord injury research, potentially bringing new hope to 40,000 paraplegics and quadriplegics across the country.

      "It is very dramatic," lead researcher Michel Rathbone, a professor of medicine at the university in Hamilton, Ont., said of the findings. "The important advance is that we've shown that nerves that normally do not regenerate at all can be made to regenerate with the body's own cells.

      "Obviously, this has the potential to be a cure, but just as it took 60 years from the first airplane flight to get to a 747 airliner, it is a giant leap." Rathbone will present the results at a Society for Neuroscience meeting in San Diego, Calif., in November.

      With spinal injuries, it is commonly thought the nerve cells are destroyed. They are not. It is the cell processes, or the long, telephone-like wires that run throughout the spinal cord, that are damaged, prompting the permanent injury. This research has the potential to reverse the damage.

      In experiments with rats, the scientists extracted enteric glia cells from the intestine, purified them, and then injected the cells into the spinal cord, where sensory nerves enter. Soon, the enteric glia began migrating, prompting the nerve fibres to follow suit, returning to normal growth.

      "This means we can now make nerve fibres regenerate through the spinal cord, which normally they would not do," said Rathbone. "Every single one with enteric glia showed a very robust growth of cells into the spinal cord. This is not just a little bit significant because this doesn't happen normally. It just does not happen."

      Rathbone pointed out there are many advantages to working with enteric glia cells, which do everything from controlling interconnections between nerve cells to covering axons, the part of the nerve cell that delivers impulses from cells to muscles. The advantages include little likelihood of rejection by the body because the transplanted cells are from the same person.

      About 50 rats were used for the research. The 40 animals that were control groups showed no response, while all 12 rats injected with enteric glia demonstrated the regeneration.

      For humans, the scientific possibilities are immense. If the technique were able to regenerate the spinal cord just two or three centimetres, said Rathbone, arm and hand movements would return. "That would turn a quadriplegic into a paraplegic and totally change their quality of life.

      "A person who is quadriplegic may not be able to feed themselves but if you could give them back movement of the hands, they can do many, many things," he said.

      The Canadian Spinal Research Organization, a group of paraplegics and quadriplegics whose goal is to find a cure for spinal injuries, has given more than $1-million to Rathbone's laboratory in the past eight years.

      "I think these findings are significant," said Ray Wickson, the group's president. "It's proving in the animal model to be successful and I can see, not tomorrow but in a few years if everything progresses the way it is going, it being used in human clinical trials."

      Wickson first heard about enteric glia cell research in the late 1980s. Convinced it might one day pave the way to a cure, Wickson approached Rathbone to begin laboratory testing.

      Among those who could be affected by Rathbone's research is U.S. actor Christopher Reeve. The actor, best known for his high-flying role of Superman, became a quadriplegic after he was paralyzed in a fall from a horse.

      Reeve, who is an outspoken advocate of cutting-edge spinal research, including studying embryonic stem cells, broke his neck in the May, 1995, accident. He has the most severe spinal-cord injury the human body can endure, leaving him without use of his arms or legs, bladder or bowel control or sexual function. He can breathe on his own only for short periods of time.

      "The promise of human trials is obviously down the road but it holds out exciting future potential," said Stephen Little, a spokesman for the Canadian Paraplegic Association. "They still have a lot of challenges but anything that could help reduce the impact of spinal-cord injuries, whether it's some kind of sensory gain or motor function gain, is just that, a big gain."

      In the future, Rathbone intends to observe animals with spinal damage over a longer period of time to see whether they also produce the same regenerating result with the injection of enteric glia cells. He also hopes to begin work on larger animals, including dogs. If all goes as planned, he believes human trials will be underway within three years.


      • #18
        Dr. Harry Goldsmith

        Harry Goldsmith, M.D.:
        Hope for Spinal Cord Injuries

        Dr. Goldsmith is a surgeon who has developed a most remarkable procedure for spinal cord injuries, Alzheimer's disease, stroke, and other neurological disorder.

        During this procedure, called omental transposition, the omentum, a nutrient-rich fatty apron covering the intestines, is laid over an injured spinal cord or brain -- with dramatic results. In the June, 1997 issue it was reported how this procedure transformed Darren Renna, who became paralyzed in a gymnastics accident and was so disabled he had to be strapped into a wheelchair. After having this procedure, he had a remarkable return of function. He is able to write and maneuver his wheelchair, and has a career as a gymnastics judge.

        Yet this procedure, which is routinely used in China and South America for cerebral palsy, Alzheimer's disease, and spinal cord injury, is inexplicably ignored in this country by neurologists and surgeons, whose patients would benefit enormously.

        For more information on omental transposition, write to Dr. Goldsmith at P.O. Box 493, Glenbrook, NV 89413 or fax 702-749-5861.

        Goldsmith HS, et al. 1999. Omental transposition for
        cerebral infarction: a 13-year follow-up study.
        Surg Neurol 51:342.

        Goldsmith HS. 1997. Omental transposition to the brain
        for Alzheimer's disease. Ann NY Acad Sci 826:323.

        Goldsmith HS. 1996. Omental transposition for
        Alzheimer's disease. Neurol Res 18:103.

        Goldsmith HS. 1994. Brain and spinal cord revascular-
        ization by omental transposition. Neurol Res 16:159.

        Goldsmith HS, et al. 1992. Axonal regeneration after
        spinal cord transection and reconstruction. Brian
        Res 589:217.

        Goldsmith HS. 1990. [Lack of atherosclerosis in
        omental arteries]. Lancet 335(8686):409.

        Goldsmith HS, et al. 1990. Regional cerebral blood
        flow after omental transposition to the ischaemic
        brain in man. A five year follow-up study. Acta
        Neurochir (Wien) 106:145.

        Goldsmith HS, et al. 1986. Increased vascular perfusion
        after administration of an omental lipid fraction.
        Surg Gynecol Obstet 162:579.

        Goldsmith HS. 1980. Salvage of end stage ischemic
        extremities by intact omentum. Surgery 88:732.

        [This message was edited by Birde on August 18, 2001 at 12:38 PM.]


        • #19
          An interesting link:

          Dr. Young, would it affect the food digesting process, if those cells are taken? Or is there too little amount needed?

          Dr.Michel P. Rathbone
          Enteric Neuron and Glia Transplantation into Spinal Cord


          Fact can be stranger than fiction - fish skin and intestines may each help in spinal cord injuries. Your mother likely told you that eating fish was good for your brains - now a group of researchers at McMaster University funded by the CSRO are finding that it may be good for injured spinal cords, too. The substances which make fish skin shiny are called purines (pronounced "pwe-er-eens"). These purines help in fish development and in spawning. Purines are also found inside all cells as building blocks of DNA and RNA, the genetic material. As well, purines are the energy currency of cells. But purines have very important roles outside cells, too. There are also chemical messengers, purines released by one cell move in the fluid outside cells taking information to other nearby cells. So, for example, purines are one of the chemicals which transmit messages from one nerve cell to another.

          Substances from fish skin may help protect the spinal cord immediately after injury: Over the last few years work from several laboratories, particularly from Dr. Rathbone's laboratory at McMaster University, has shown that purines outside cells play important roles in spinal cord and brain injury. When cells in the nervous system are damaged they release large quantities of purines. Purines help protect cells from further damage. As well, purines carry special messages to cells surrounding the damaged area. This makes them release "trophic" substances which help repair nerves in the brain and spinal cord.

          Unfortunately, in most cases not enough purines are released and substantial damage results. In research funded by the CSRO, Dr. Rathbone and his colleagues have tried to increase the purine levels after spinal cord injury (SCI). They found that when the synthetic purine 4-{[3-(1,6dihydro-6-oxo-9-purin-9-yl)-1-oxypropyl]amino} benzoic acid, also called leteprinim potassium, is given following SCI, the effects of the injury are minimized. Currently they are attempting to find how exactly this substance improves the outcome of SCI. "We are attempting to boost the naturally occurring protective and repair processes in the spinal cord, said Dr. Rathbone. "We are using a modified purine which is even more effective than those found in fish skin and in the nervous system".

          One of the types of cells which the purines affect are known as glia. Glia are supporting cells in the nervous system. There are several types of glia. One type, astrocytes, has many functions. Astrocytes form the scars in the nervous system after injury. But astrocytes can also make the protein trophic factors which help the nervous system to recover after injury. Purines make astrocytes synthesize and release more trophic factors. Rathbone and his colleagues think that astrocytes and another type of glia, microglia or scavenger cells, are important in helping the purines to reduce the effects of spinal cord injury.

          Cells from the intestine may help regeneration of nerves in the damaged spinal cord. The problem of repairing the injured spinal cord long after it has been injured is a different problem, but one that nevertheless also may involve glia. After the spinal cord is injured a very complicated series of processes occurs involving nerve cells and several types of glia. The overall result of these is to prevent regrowth of nerve cell processes across the region of damage. However, recently glia from the nerves at the back of the nose have been transplanted into the spinal cord. The glia from the nose then migrate, literally crawling up and down the spinal cord. In doing so they seem to make paths for regenerating nerve cell processes to follow, as though they are towing the nerve processes along. But there are not many glia in the nose, so the use of this technique in human SCI is potentially limited.

          Rathbone and his colleagues, funded by the CSRO, have taken another approach. The intestine has a nervous system which makes the gut move food along it. The intestinal nervous system contains glia which are similar to astrocytes. Pamela Middlemiss and Shucui Jiang, working with Dr. Rathbone, isolated and purified the glia cells from the intestine of rats. They then added a substance to mark them and were recognizable from the staining. Now these researchers are trying to determine whether these glia from the gut will release trophic factors which make the nerve cell processes grow as do the glia from the nose.


          • #20
            dimitriy, I don't think that removal of a segment of the intestines (or whatever they did to remove the "intestinal glial cells") would necessary compromise the function of the intestines in the long run. We have more intestine (22 feet of it, for that matter) than we must have). However, as I pointed out, the surgery itself is not trivial and it can have complications. Wise.


            • #21
              Wise, do you think this could replace OEG or work just as well? Certainly the surgery would be less complex. I suppose I am growin impatient. But sometimes I get tired of reading about all these breakthroughs with nothing coming from any of them very quickly. I have just been bummed out lately, first about Bush's stem cell decision and then about Gary's death. It all makes me so angry. Bill


              • #22

                I think that it is too early to tell whether intestinal glial cells are better than OEG or can substitute for them.

                Your question brings up a more important question... where are all these cell transplant experiments taking us and what is likely to happen? As you know, the Proneuron and Diacrin trials are continuing to recruit patients. Alexion is planning a porcine OEG trial in 2002. Layton is planning to do more trials with their human teratoma neuronal cell line (which is actually producing very promising results in animal studies, indicating that they will produce neurons that connect with other cells in the spinal cords of rats). With the freeing up of federal funds for human embryonic stem cells (even the limited number of lines), we can even start thinking about the possibility of human embryonic stem cell trial in the United States (and they have already started in Russia). Where will we be in one year, two years, perhaps three years?

                By next year, the Proneuron trial on activated macrophages will have shown that these cells can be safely transplanted into human spinal cords... one or more patients are likely to show some beneficial response. Proneuron will no doubt expand the trial into a phase 2 trial in the U.S. for subacute spinal cord injury and probably initiate a chronic human spinal cord injury trial. In the latter, for example, I am thinking that some centers will find it justifiable to go ahead and transplant activated macrophages into the spinal cords of people who are getting untethered and decompression of the spinal cord.

                Hopefully, the Diacrin trial will have shown that the porcine stem cells can be safely transplanted and none of the patients show deterioration of function. If there is even a hint of improvement in the patients, I think that Diacrin will expand the trial into a phase 2, comparing perhaps two different kinds of cells. One possibility is a trial that compares human and porcine cells stem cells. That is one of the reasons why I have been speaking out in recent weeks on this subject because I think that a clinical trial with human embryonic stem cells is imminent whereas adult stem cells may be a few years off.

                Layton may be planning to transplant their teratoma cell line into human spinal cord. They have already done so in stroke patients and they recently received additional funding for clinical trials. Two well-known laboratories (Paul Reier's and Alan Privat's labs) have found really promising results in animal spinal cord. As soon as those papers are published, they may decide to go for a trial.

                Alexion is likely to start a porcine OEG trial. I think that they are applying right now to do so with the FDA and it is taking a long time because these are xenotransplants. I know that there are serious attempts in Spain and Miami to initiate a human adult autograft OEG trial. If they are able to get federal funding for the latter (which incidentally would need to be funded by the federal government since no company would profit from adult autograft therapies), that trial may start soon.

                In the meantime, the Russians and Chinese will be pushing the research in their countries, possibly publishing results here in the U.S. and therefore driving the research here. So, I think that 2002 will be the year of cell transplant therapies for spinal cord injury.



                • #23
                  Placing a flap of intestinal tissue onto an injured site is too haphazard. The tissue, which is not purified, may not be healthy or contain high enough amounts of the specialized cells required for regeneration may be why omentum transplantation produces such inconsistent results. Dr. Rathbone's technique isolates the specialized cells within the omentum/intestinal material, purifies them and puts the right amount into an injury site. I would not be suprised if his technique, when applied to humans, produced higher and more consistent recovery rates than those involving whole omentum transplantation alone.

                  J Neurol Neurosurg Psychiatry 2001 Jul;71(1):73-80
                  Prospective study of omental transposition in patients with chronic spinal injury.

                  Duffill J, Buckley J, Lang D, Neil-Dwyer G, McGinn F, Wade D.

                  Department of Neurosurgery, Wessex Neurological Centre, Southampton University Hospitals Trust, Tremona Road, Southampton SO16 6YD, UK.

                  OBJECTIVES: This prospective study was designed to assess the effects of omental transposition in patients with a chronic spinal injury. METHODS: Neurological status was established to be stable and multiple baseline across patient studies were done preoperatively and repeated postoperatively. Assessments included activities of daily living (ADL), functional ability, degree of spasticity, motor power, sensation, pain perception, urodynamic studies, electromyography, sensory evoked potentials (SEPs), and infrared thermography to measure peripheral and general skin vascular responses. Each patient had MRI. Assessments were done at 3, 6, and 12 months after omental transposition in 17 patients. RESULTS: The detailed assessments failed to show significant improvement, although some patients showed minor objective and subjective change in some categories. Neurological deterioration occurred in one patient. There were 20 surgical complications including urinary tract infection, deep vein thrombosis, wound infection, and incisional hernia. CONCLUSIONS: Omental transposition has not been shown to improve neurological function in 17 patients with chronic spinal cord injury, and continued use of this operation in this situation is not supported by this study. Further advances in spinal cord repair may utilise the pedicled omental graft to provide an alternative vascular supply, but its current use should be limited to experimental models.


                  • #24
                    Chick sox10, a transcription factor expressed in both early neural crest cells and central nervous system.

                    This may be a way to respecialize the cells: add the human version of the Sox10 ortholog (hSox10?) discussed in this study to a culture of intestinal cells and allow them to divide. cSox10 is expressed in the developing CNS and is possibly assimilated, not lost, when cells undergo neuronal differentiation. With a large enough cSox10 culture, the intestinal cells may "bow to the peer pressure" [or "feel pressured", I don't know the scientific term [img]/forum/images/smilies/wink.gif[/img]] and go down the neuronal path instead.

                    The hSox10 may work similarly to help guide the cells down the proper path when inserted into the spinal cord and allow neural cells to be developed. The environment should produce enough signaling factors to tell the intestinal cells which type of neural cells to create.

                    Just my guess. :-)


                    Brain Res Dev Brain Res 2000 Jun 30;121(2):233-41

                    Chick sox10, a transcription factor expressed in both early neural crest cells and central nervous system.

                    Cheng Y, Cheung M, Abu-Elmagd MM, Orme A, Scotting PJ.

                    Nottingham Children's Brain Tumour Research Centre, Institute of Genetics, University of Nottingham, Queen's Medical Centre, NG7 2UH, Nottingham, UK.

                    Human SOX10 and mouse Sox10 have been cloned and shown to be expressed in the neural crest derivatives that contribute to formation of the peripheral nervous system during embryogenesis. Mutations in Sox10 have been identified as a cause of the Dominant megacolon mouse and Waardenburg-Shah syndrome in human, both of which include defects in the enteric nervous system and pigmentation (and in the latter, sometimes hearing). We have cloned a chick Sox10 ortholog (cSox10) in order to study its role in neural crest cell development. This cDNA reveals a 1383 bp open reading frame encoding 461 amino acids which is highly conserved with human SOX10 and mouse Sox10. In situ hybridization showed cSox10 is expressed in migrating neural crest cells just after the zinc finger transcription factor Slug, but is lost as cells undergo neuronal differentiation in ganglia of the peripheral nervous system. In addition, cSox10 is expressed in the developing otic vesicle, the developing central nervous system and pineal gland.

                    PMID: 10876038 [PubMed - indexed for MEDLINE]

          's worse than we thought. it turns out the people at the white house are not secret muslims, they're nerds.


                    • #25
                      I am hoping that Dr. Rathbone can come and visit this forum to answer the many questions that have come up. Wise.


                      • #26
                        just curious

                        what do doctors wait to publish their results? Why wait until November if he has enough information talk about it now in the newspaper?


                        • #27
                          I think that Dr. Rathbone and his colleagues have probably submitted the paper for publication but it takes months for the paper to be reviewed and published. In the meantime, they are presenting the data at the Society for Neuroscience (this allows other scientists to hear about the data). Wise.


                          • #28
                            Dr. Young, were you able to attend or did you see a presentation regarding Dr. Rathbone's work?


                            • #29
                              Yes, I saw their posters both at the Neurotrauma Society and the Society for Neuroscience meetings. I think that it is interesting and important work. The cells seems to act like olfactory ensheathing glial cells. Even the posters did not present all the information that is necessary to judge the validity of the results.

                              In my opinion, the above news article is not providing an accurate view of the research. Statements like the treatment is allowing 100% success... the recovery of function is not anywhere close to 100%. Also, please understand that the work focusses on the regeneration of a spinal root into the spinal cord and not regeneration of spinal tracts in the spinal cord. Similar results were reported for OEG cells for root regeneration over five years ago.

                              I am not saying the above to put down this study which I think is important and an important contribution. However, people are jumping to conclusions here about spinal cord regeneration from a limited study that is eamining regeneration of spinal sensory fibers back into the spinal cord.

                              Publication of work in a peer-reviewed journal means that it has passed the critical review of other scientists. Most journalists are not particularly critical and many do not present a balanced view of a therapy. There may be all sorts of things wrong with a study and it may still be presented as a miraculous cure in a newspaper. Publication in a scientific journal also presents the data in detail so that we can judge the results.



                              • #30
                                Thanks Dr. Young, but as usual your answers leave me with a few more questions.

                                First, in your recent article describing level of injury you mentioned that a burst fracture of C five would damage the C4 root (it's been a couple of weeks since I read the article so I could be wrong), and that in time the roots should recover to a degree. How are the spinal cord roots different from the spinal cord itself? And according to the example mentioned above, do the roots regenerate and heal to restore function? Is this the reason why most people gain some function after injury, because the roots are in the process of healing?

                                Second, since the cells are derived from our own bodies, why do we need 2 or 3 sets of animal data to move forward into trials? Are the cells being modified (I was under the impression they were not)?

                                Are you aware of any other institutions who are working on something similar using these intestinal cells?