Conference Summary of the 1st International Association of Neurorestoratology Annual Conference (IANRAC)

The First International Association of Neurorestoratology Annual Conference (IANRAC) was held on May 15-18, 2008 in Beijing, China. It was sponsored by the International Association of Neurorestoratology (IANR), and co-sponsored by the Beijing Hongtianji Neuroscience Academy,  the Neuroscience Institute of Taishan Medical University, and the  Chinese Journal of Reparative and Reconstructive Surgery. The  representatives came from China, United Kingdom, United States, Spain, France, Australia, Japan, Argentina, Jordan, and the Hong Kong Special Administrative Region.

With  the purpose of “establishing neurorestoratology and promoting basic and  clinical research on neurorestoratology” and with the theme of  “Neurorestoratology”, the conference reviewed the past, faced the  present, and prospected the future on neurorestoratology; carried on the  discussion on related issues of neurorestoratology, discipline  construction, and the impetus strategy as well. Many world renowned  experts in the field gave exciting special reports, including basic and  clinical research on neurorestoratology, basic and clinical research on  peripheral nerve restoration, cell transplantation on spinal cord  injury, topics on stem cells, various intervention strategies on  neurorestoratology, basic research on neurorestoratology, and clinical  application of cell transplantation.

As  the only international specialized academic organization in this field,  the IANR has been given a historical mission, professional tasks,  social responsibility, and the goal of meeting patients' expectations.  The successful conclusion of the 1st IANRAC moved the new subject,  neurorestoratology to the international academic platform. The  conference also elected the 1st Council of the IANR for a term of 3  years.

Ⅰ. Association and Subject Creation

Professor  Huang Hongyun, as the president of this conference’s organizing  committee, emphasized in his speech that Neurorestoratology is a  sub-discipline of neuroscience which studies neural regeneration,  remodeling, restoration and functional recovery. Its purpose is to  promote the recovery of neural function of all patients with neural  degenerative diseases and damages. Its strategies are to stress the  close combination and organic integration between basic research and  clinical research, to emphasize the solution of practical problems of  clinical medicine and preventative medicine, and to insist on always  setting the direction according to clinical research while constantly  enriching the knowledge gained from basic research. Its main goal is to  promote a coordinative effort to improve both basic and clinical  research rapidly; to break the barrier between basic research, pharmacy  development and clinical medicine while establishing the direct links  between them; and to shorten the process from bench to bed, thus  transferring the basic research achievements of neurorestoratology into  new methods for the clinical treatment and faster patient benefit from  medical, scientific, and technological advances.

Establishing  the IANR would create a broad professional platform of exchange for  global basic scientific researchers and clinicians working in the neural  restorative field. It would be beneficial to increase the depth of  basic theoretical research related to its subjects, to improve and  perfect the intervention strategies, to raise the effectiveness of the  restorative functions, and to promote the development of  neurorestoratology.

Ⅱ. Topics on Olfactory Entheathing Cells

The world renowned experts in the field of olfactory ensheathing cell research came to Beijing to attend this conference. Prof. Almudena Ramón-Cueto from Spain  gave a presentation titled, “Auto-transplantation of olfactory bulb  glia to repair spinal cord injuries: clinical perspectives”. She pointed  out the following: traumatic spinal cord injuries (SCI) have a big  impact on our society. Several attempts have been made to find a repair  strategy in experimental animals that could be translated into human  application. In 1990, researchers started a series of experiments, and  their studies demonstrated that adult OB-OEG transplants could  functionally and structurally repair spinal cords completely sectioned  for adult mammals. To elucidate the feasibility of OB-OEG use in humans,  they carried out animal experiments with primates. The studies showed  that ex vivo expansion of one single primate adult OB-OEG bulb for up to  2.5 months in vitro could yield enough OEG (2×10¹⁰)  to guarantee both auto- and allo-grafting, with excess cells to be  stored in banks for future therapeutic use. In addition, they have  developed medical and surgical procedures for autologous (and  heterologous) OEG transplantation in rhesus monkeys, compatible with  human application. Strikingly, in the first paraplegic monkey  transplanted autologously with OB-OEG using their technique, they  observed a tangible functional recovery by objective neurophysiologic  assessment, and step-training on a treadmill promoted neurological  functional recovery. As an important marker of olfactory ensheathing  cells, P75 positive rate accounted for about 35 percent in Ramón-Cueto’s  laboratory. She believed that this was a major part of executive  function. She summarized that olfactory ensheathing cells have four  unique abilities to repair nerve injuries as follows: can be used for  autologous transplantation, can integrate with other natural glial  cells, will not form tumors, and can express a variety of regeneration  associated factors. Professor Meng Inn Chuah from Australia introduced  the restorative functional mechanism of olfactory ensheathing cells: ①OECs express growth factors and membrane-associated molecules that are known to promote axon growth. ②OECs are able to mingle with astrocytes, regulate GFAP expression in astrocytes mediated by FGF family member. ③OECs and Microglia interact in the inflammatory response, OECs function as phagocytes. ④OECs  express cytokines and molecules of the innate immune system such as  Cebpb, Lyz, Ccl2, Gro1, Ctgf for example. As a scientist having a  tremendous impact on this field, Geoffrey Raisman, the researcher from  the British Royal Academy of Sciences, proposed the tunnel theory of  nerve regeneration. He explained the complexity of neural remodeling and  the importance of neural rearrangement. He believes that cell  transplantation strategy should be used in clinics, and more work should  be done. Researcher Ying Li, who worked in his lab, introduced their  work in which they had transplanted OECs into the damaged spinal cord to  promote neural regeneration. The transplanted OECs could help restore  the integrity of the original pathway, and promote some functional  recovery. She suggested that it was better to perform cell  transplantation with all types of cells under physiological status. She  agreed that people should use different animal models of spinal cord  injury for different research purposes. Wei Kai-bin (Shandong)  proposed that the combination of OEC transplantation and  methylprednisolone might effectively treat acute spinal cord injury. Liu  Yan (Beijing)  studied the Low-affinity NGFR positive OECs in the human fetal  olfactory bulb. She compared fetal olfactory ensheathing cells'  development in rats and humans and discussed their distribution,  effects, and culture technique. Her data strongly suggests that  p75-positive OECs participate in glomerular formation in the fetal human  olfactory bulb. This behavior differs from OECs in the rat olfactory  bulb. About 40% of the cells expressed p75 in  culture. This result is similar to the results of OECs cultured in  primates by Professor Ramón-Cueto. Professor Alan Mackay-Sim’s (Australia)  presented the experience of three patients with chronic spinal cord  injury receiving autologous transplantation of adult OECs from olfactory  mucosa after three years follow-up, and suggested that the procedure of  OECs autografting transplantation was safe. Professor Huang Hongyun (Beijing)  reviewed the functional restoration by OEC transplantation for spinal  cord injury, ALS, cerebral palsy and stroke in 1,255 cases. All the data  strongly suggests that OEC transplantation for these damages and  diseases is a safe and effective procedure. Zheng Zuncheng (Shandong) reported the results of clinical treatment of SCI with OEC transplantation. He suggested that the ASIA  rating scale could not accurately reflect the change of a patient’s  quality of life, so a new evaluating scale needs to be designed.

Ⅲ. The Theory of Evolution and Neurorestoratology

Professor  Wang Dajue (British) explained the restorative mechanism of a spinal  cord injury by evolution theory. Spinal cord injury is part of biology,  so it is closely related to the evolution theory. It is unwise to ignore  the evolution theory; both the species and the cell germination are  controlled by molecular evolution. Evolved into the more advanced stage,  the participation of factors was increased, thus control was more  difficult. From the viewpoint of evolution theory, the cells with  regenerating ability in the human body have to be the most ancient  structures in the mature nervous system (the olfactory system, the  limbic system, and the network structure). According to Professor Wang  Dajue’s observations, most patients treated by Professor Huang Hongyun’s  OEC transplantation sweat on the day after surgery; so this was the  short-term response to the treatment. The restorative functions still  existed on long-term follow-up. He analyzed that the older the system,  the easier it is to be restored. The higher developed species are less  likely to be restored. The order of easily restoring spinal cord injury  is precisely the same as the order of treatment preferred. The first  priority is survival; the second is improvement in the quality of life.  He believes that we should rethink whether the strategic principle that  overemphasizes body movement is correct.

Ⅳ. The Central Nervous Restoration

Professor Liu Enzhong (Heilongjiang)  introduced the pathological process and the changes in molecular  biology following an injury to the central nervous system. The  self-protective body response occurs with injury, so he explored the  time window of intervened treatment and the prospects of restoration in  CNS. He believes that neurorestoration of CNS should include not only  nervous structure reconstruction, but also neurological functional  recovery. Professor Luan Zuo (Beijing)  reported the strategies on pediatric neurorestorative intervention.  They selected eleven cases of children with cerebral palsy accompanied  by visual impairment, and did human neural progenitor cell  transplantation. Three to six months after transplantation, they found  that the children had visual functional progress. Their primary  conclusion was that the neural progenitor cell transplantation is a safe  and effective method for children with cerebral palsy accompanied by  severe visual impairment.

Ⅴ. The Peripheral Nervous Restoration

Professor Zhang Shaocheng (Shanghai)  reported the experimental and clinical research of the side-to-side  anastomosis between the nerve tracts. It has been found that the  clinical effect is better by using side-to-side anastomosis than by  using broken ends anastomosis. This method was effective for the  patients with brachial plexus injury, peripheral nervous injury and  local spastic cerebral palsy. Professor Liu Song from French Pasteur  Institute reported his experimental therapeutic research about brachial  plexus injury. After establishing the rat C6, C7 dorsal root cut model,  peripheral nerve tissue transplantation was done below the injured  region. Histological data showed that grafts could go through the strong  GFAP positive gliosis region and measurement of toe to toe distance and  the weight distribution of different toes improved after  transplantation.

Ⅵ. The History and Current State of Neurorestoratology

Dr. Chen Lin (Beijing)  reported on many important historical events and scientists who have  conducted basic research of neurorestoration over the last 100 years. He  showed the neurorestorative intervening strategies’ processes of CNS on  a panoramic display. Professor Huang Hongyun (Beijing)  believes that the clinically exploratory treatment of neurorestoration  was the major driving force for promoting the development of  neurorestoratology. Neurological functional recovery and improvement in  the quality of life have become realistic goals through neurorestorative  intervention strategies. Though embryonic and fetal brain tissue  transplantation were controversial, they were critical to the  development of clinical neurorestorative treatments. Cell  transplantation; biological, genetic and tissue engineering; medicine  and other physical factors; and neurological rehabilitation’s  intervention strategies might help neurological functional restoration.  So it should be objective and fair to evaluate these achieved results  through active exploration. Scientists and physicians should focus on  how to improve the neurorestorative effect in the future. The strategies  were the following: (1) optimizing results by combining the methods  which have been proven effective, and (2) actively exploring new  methods. Professor Wise Young (USA) reported the functional recovery of spinal cord injury and assessing methods, such as ASIA,  SCIM II, and WISCI. He introduced the application prospects of cell  transplantation using many kinds of cells and focused on the advantages  and the mechanism of OEC transplantation to restore spinal cord injury,  prospects of the stem cell applications, and the distribution of China  SCI Net. He believes that combination therapies can be approved if the  combination therapy is more effective than each individual component on  its own. The aspects of cell transplantation which should be paid  attention to are safety, quantity, efficacy, side-effects, and  complications. As for the question of how to design the control group,  Young's reply was, “This is a very good reason, because it is hard to  explain the effectiveness of the treatment without control. However, is  the design of control group the only way to explain effectiveness? We  have not seen the data with control over years, such as organ’s surgical  resection or transplantation. Of course, because there is no sham  control, people will believe that the effect of functional improvement  is the process of spontaneous recovery. The design of sham surgery is  really a very complex issue.”

Ⅶ. Topics on Stem Cells

Professor Gustavo Moviglia (Argentina)  proposed that the combination of adult neural stem cells with the  intervention strategies of protective immunity have an effect on  patients with spinal cord injury, amyotrophic lateral sclerosis,  pseudo-hypertrophic muscular dystrophy and Becker muscular dystrophy.  Bao Jian-ling (Beijing)  reported the culture and identification of human fetal olfactory stem  cells in vitro. She also analyzed the misuse of the term, neural stem  cells. Professor Ding Jigu (Hubei)  reported his experiment on the differentiation of the mesencephalic  neural stem cell by GDNF and IL-1 β in vitro-induced. The M-NSC could be  successfully induced and differentiated by GDNF, IL-1 β or both in  vitro into a sufficient number of dopaminergic neurons that are both  morphologically and functionally mature. Professor Chi Feng and Xu  Yinghui (Liaoning)  suggested that neural stem cell transplantation done under  sub-hypothermic conditions was more effective than neural stem cell  transplantation done at normal room temperature. Associate Professor  Liang Peng (Heilongjiang) proposed that neural stem cells can promote the neurorestoration and remyelination for spinal cord injury. Wang Jiming (Tianjin),  chief physician of Chinese medicine, introduced the effect on  proliferation and differentiation of the bone marrow stromal cells into  nervous cells by application of traditional Chinese medicine. He also  reported on the beneficial exploratory treatment of motor neuron disease  by combining bone marrow stromal cells and traditional Chinese  medicine. During the discussion, Professor Huang Hongyun stated that the  definition of neural stem cells used by some scholars is inaccurate.  The effects of neural stem cell transplantation reported in basic and  clinical research are mainly from mature functional cells with  transplantation, but not from neural stem cell transplantation. Neural  stem cells play two main roles: one is the functional gene transfer to  neural stem cells in vitro causing the cells with transferring  functional gene from stem cells to proliferate and differentiate after  transplantation; the second is that the stem cells induced to  differentiate functional neurons or glia in vitro or in vivo. But the  process of inducing stem cells in vivo is still unknown. Although  currently there are still some differences of viewpoint about the  definition and identification of neural stem cells, it is generally  agreed that neural stem cells have three unique characteristics. One is  that they keep the marks of primeval neural cells, such as Nestin. The  second is that they do not have the marks of mature neural cells. The  third is that they can self-renew, self-replicate, differentiate  multipotentially and stably continue to passage, and later differentiate  into nervous tissue in vitro. Neural stem cells are one of the most  important potential intervention strategies for neurorestoration. In  order to unite the scientific community to correctly identify and  exploit stem cells’ role and value, it is urgent for neurorestoratology  to create a standard definition and identification methods for neural  stem cells. Achieving this will help to advance and increase the amount  of stem cell research.

Ⅷ. The Comprehensive Intervening Strategies for Neurorestoratology

Professor Wagih S EI Masry (United Kingdom)  proposed that spinal cord injury should be treated conservatively, so  that patients can maximize their nervous functional recovery. But other  doctors suggested that he not only show a case report, but present all  of the data. Professor Albert Bohbot (France)  introduced experiences with laser acupuncture that promoted functional  recovery. He preliminarily confirmed that the combination of laser  acupuncture and rehabilitation training for patients with chronic spinal  cord injury played a very important role in functional improvement  after OEC transplantation. Dr. Tang Zhouping (Hubei)  introduced the concept of biologically engineering materials and its  future application prospects in the central nervous system. Professor Wu  Chengyuan (Shandong)  mainly introduced his research during which fetal nervous cells and  transgenic cells were transplanted into the striatum of a primate monkey  with Parkinson’s disease. The results showed histological and  functional improvements in the subjects. Dr. Li XiangDong and Professor  Hui Guozhen (Jiangsu)  reported on the application of the amniotic epithelial cell and the  transfer of BDNF amniotic epithelial cell transplantation to treat  primates with acute spinal cord hemitransection. The motor functions in  the cell transplantation group improved significantly better than the  control group, and best in the transfer of BDNF amniotic epithelial cell  group. Dr. Renhui Chen (TianJin), on behalf of Professor Feng Shiqing,  reported that a low-dose X-ray promoted neurorestoration in rats with  SCI. Professor Xu Shaoting (Beijing) proposed that promoting motor  neurorestoration by the current strategies of cell transplantation  should still be under suspicion. The key points for restoration of  spinal cord injury are to provide the channels of axon growth, nerve  growth factors, and to remove the inhibition factors. Dr. Zhu Zhenzhong (ShanXi),  on behalf of Professor He Xijing, reported on the neural protection and  regeneration by the injury reactive astrocytes in the subventricular  zone (SVZ) of adult rats. Professor Gang Li (Hong Kong)  proposed the new technological concepts of distraction osteogenesis  which can increase brain blood supply; thereby improving the functions  for patients with stroke.

Ⅸ. Patients' Wishes

As  the representative of patients with spinal cord injury, Mr. Wen Jun put  out the following call to action: “Currently it is more realistic for  us to improve the quality of life and reduce complications if the dream  of walking again cannot be achieved. I hope that future research can  achieve greater success and I believe that scientists should present  patients with realistic expectations.”

At the conclusion of the conference, attendees all agreed to make the International  Association of Neural Restoration (IANR) Spinal Cord Injury Functional  Rating Scale, SCI-FRS (Seeking Suggestions), International Association  of Neural Restoration (IANR) ALS/MND Self-Assessment Scale (Seeking  Suggestions), and The Neural Restorative Cell Transplantation Clinical  Practice Principle (Seeking Suggestions) public and seek more  advice and suggestions from other experts in the field. The IANR  promised to donate one million Yuan to support neurorestorative  treatments for those who suffered spinal cord injury and brain damage in  the Wenchuan earthquake in southwest of China. The IANR also declared  that the 2nd IANRAC will be held in Beijing on April 24-26, 2009.

（Collators:  Hongyun Hung, Lin Chen, Yan Liu, Jingli Cao, Bingqing Zhang, Jia Liu,  Yali Kang, Jianling Bao, Irene Chen, Daniel Huang.  Proofreader: Mr.  John Heilman(USA)）