INTRODUCTION
Stem cell therapy offers new hope to treat the many currently untreatable or no longer treatable diseases in conventional medicine, including autism spectrum disorder, chromosomal disorders, diabetes mellitus, even human immunodeficiency virus (HIV). Certainly, success or failure depends very much upon a thorough understanding of the disease in question and also the mechanisms by which stem cell therapy is expected to function optimally.
Without a doubt, extensive basic science is needed in order to achieve this. It is important for us to know the past, to understand the present, and thereby to strategize and plan research in regenerative medicine for us to know the past, to understand the present, and thereby to strategize and plan research in regenerative medicine for the future. Admittedly, this "hot" area will be the focus of continuing political debate among policymakers and the public. There are proponents of embryonic stem cells, adult stem cells, and xenogeneic stem cells.
All these have and will continue to go through a public examination on moral, ethical, and funding issues. Stem cell research currently focuses on exponential rate but the progress in therapeutic applications is, however, slow. The protocol of live cell therapy-- which uses fresh cells, frozen cells, and or lyophilized cells from animal sources--- have been used for the treatment of untreatable diseases in conventional medicine for more than eighty years.
In our Malaysian case studies, we use the latest form of live cells, fetal precursor stem cell xenotransplants derived from fetal rabbits, and prepared by the state of the art primary tissue cultures. Regrettably, there has been a dearth of fundamental research in live cell therapy currently that is needed to build on the prolific research work done by scientists in the twentieth century.
Stem cell therapy is now incorporated in the new branch of medicine called "regenerative medicine". This is a new branch of medicine that deals with the 'process of regenerating human cells. tissues, or organs to store its established normal function.' It also includes stimulating the body's own repair mechanisms to heal dysfunctional tissues or organs.
Regenerative medicine now goes beyond this, it includes the possibility of growing tissues and organs in the laboratory and safely implanting them when these corresponding tissues/organs cannot be healed by the body's own repair mechanisms. Cell-based therapy with human cells and fetal precursor cells from animal sources is at the heart of regenerative medicine.
This is an exciting research field, and there has been an exponential increase in translational research in tissue engineering and molecular biology to support this branch of medicine, which will be increasingly important in the years to come.
Which forms of stem cells will surface as the most viable option to treat certain incurable diseases and in certain patients will depend on the results of applied and fundamental research. But it is the public that will ultimately decide based on what they perceive to be the safest and the most effective protocol to be used to treat those diseases that require the regenerative medical approach.
DEVELOPMENT OF CELL-BASED THERAPY FROM THE EARLY TWENTIETH CENTURY
The knowledge of medicine continues from Virchow's cellular pathology in the late 1900s teaching us about the characteristics of diseased cells, progressing to Alex Carrell's (the father of cellular biology) poignant demonstration of immortality of cells. Carrell showed that you can keep alive an organ in tissue culture as long as one keeps putting in fresh embryonic cells of the corresponding organ in the culture medium. He did that on a fowl's heart for more than thirty years, only to stop the experiment following public disquiet.
This progress was followed by Dr. Paul Niehans's cell therapy using fresh cells from fetal and young animals and implanting corresponding organ cells to treat diseases in patients (chapter 2: historical perspectives). More than eighty years have now passed since cell therapy was used by physicians. Bone marrow transplantation using adult autologous and allogeneic cells are now increasingly being used. Adult cells from the umbilical cord, embryonic-like cells (induced pluripotential stem cells) to replace the ethically problematic embryonic cells are now being studied.
CELL-BASED THERAPY TODAY
The classical live cell therapy using live stem cells from animal sources continues today-but not in mainstream medicine, except in a few countries. Fresh cells are still used in Europe. The fetal precursor stem cell xenotransplants derived from primary tissue culture are the latest forms of cells used currently in the classical protocol, which are administered without immunosuppression.
The underlying principle of classical live cell therapy has been "LIKE CURES LIKE'. This is based on the concept of organ specificity, which means dysfunctioning organs must be treated by stem cells of the same type as that organ. All the two hundred or more stem cell types may be needed for regenerative medicine, and it is possible to manufacture them from animal sources.
REGENERATIVE MEDICINE: FUTURE PERSPECTIVES
The road leading to therapeutic applications long, requiring extensive basic research. This is because of the high burden of proof that is needed to show that a pluripotent source of stem cells is safe and necessary. Preclinical studies must be successfully completed. Having passed that stage, clinical trials can only then be started.
It may take many years before a protocol can be accepted as safe and effective for clinical use. The route toward the clinical application of human-based stem cells from the bench to the bedside is tortuous and unpredictable. Take the case of embryonic cells. It held a lot of promise for treatment for degenerative conditions such as Parkinson's disease in the early twenty-first century. Hitherto, a safe and acceptable protocol is not forthcoming.
For patients with untreatable/no longer treatable diseases in conventional medicine, in the future, the protocol of live cell therapy using fetal precursor stem cell xenotransplantation is an option that is available.
Preclinical and animal experimentation have been extensively done and published for all forms of live cells used in the past-unfortunately, mostly in the non-Anglophone media. Hence, until a safe and effective protocol of autologous or allogeneic stem cell transplantation using human cells is available for clinical application, patients with untreatable conditions in contemporary medicine will continue to seek treatment not available in the mainstream. The classical form of cell therapy that has been used by physicians for more than eighty years will continue to be available in the future for those who can afford it.
A very exciting area in the field of regeneration medicine today is the area of bioengineering, specifically tissue engineering. Currently, many patients are receiving treatment for the following conditions:
- Joint problems (e.g., using autologous chondrocyte implantation to renew damaged cartilage and bone) heart problems (cardiomyocytes to heal post-myocardial infarction patients)
- Neurological diseases (e.g., Parkinson's disease with neural precursor cells)
- Oligodendrocytes derived from embryonic stem cells to treat spinal-cord injuries
- Eye problems (such as macular degeneration)
Many of these are still in the clinical trial stage. What is needed is a better understanding of biological mechanisms, which will enable better results of regeneration with the use of these human-based cells. Cell-based therapy using human stem cells will be increasingly used in the future to treat diseases that have no solution in contemporary medicine.
In reality, the experience with live cell therapy in treating untreatable diseases is years ahead of that of stem cell transplantation using human-based cells. Books and published reports can be found in PubMed.
Treatment for aging diseases and revitalization is already legendary. Millions of patients have received treatment, and this will continue to be sought after. The following are some of the conditions that have been treated with live cell therapy:
- Diabetic complications (nephropathy, retinopathy, peripheral artery diseases)
- Juvenile diabetes
- Hypoendocrinopathies other than diabetes mellitus
- Autoimmune diseases
- Hyperfunctioning immune system
- Genetic (such as Duchenne muscular dystrophy)
- Chromosomal disorders (e.g., Down syndrome, Turner syndrome)
- Brain damage in the newborn
- Cerebral palsy
- Mental retardation
- Various types of cancers
- Skin burns
- Broken bones
AGING DISEASES AND ANTI-AGING
With demographic change whereby population aging is reported in most countries of the world cell-based therapy for aging diseases and anti-aging is increasingly being sought after. Revitalization regeneration is a coveted wish from time immemorial. Now it is the desire to prolong youthfulness (or 'youth span') and not just LIFE SPAN. Physicians are seeing a trend whereby their patients are slicing of ten to twenty years of their biological age with their anti-aging protocol.
Treatment of aging diseases and revitalization involves an integrative biological treatment where patients are also receiving biomedical assessment and treatment. They may be given nutrients, hormonal, botanicals, and undergo detoxification if indicated. Cell extracts in the form of eco-ultrafiltrates are marketed. Extracts of any organ cells containing peptides less than 10,000 daltons are available. These are building blocks for the body and are categorized as Nutritionals. These are taken by mouth but can also be given through injections. They can be complemented with fetal precursor stem cell xenotransplantation.
RECONSTRUCTIVE MEDICINE
This is an exciting research field that has merged with regenerative medicine. This was born from the inability of organ transplantation to make a substantial contribution in the treatment of end-stage organ conditions such as renal failure, myocardial failure, liver failure, etc. The idea of replacing diseased organs with artificial organs has been around for more than three decades. In reconstructive medicine, nonfunctioning organs and tissues in the human body are to be replaced by artificial ones using autologous stem cells to seed on animal-derived scaffolds or on prosthetic biodegradable materials such as biopolymers, which serve as templates for these cells.
We are getting reports of successful implantation of the reconstructed bladder, trachea, and parts of the face, etc. By using scaffolds and autologous stem cells, researchers aim to assist the healing process and also lower the risk of immune reaction. Regeneration of organs and parts of the body such as kidney, bladder, urethra, esophagus, cartilage, muscles, trachea, salivary glands, bone, vessels, and lungs have been successful.
Organs-including heart, nerves, liver, and pancreas-are made using embryonic stem cells (ESCS) or adult stem cells and biomaterials as scaffolds. These research initiatives are being carried out in the USA with a large number of multidisciplinary scientists[5). There had been a highly publicized case that involved a spina bifida patient who had an artificial bladder made using his own stem cells ten years ago, and the patient is currently doing well.
The research being done by this center is truly phenomenal, and the success is expected to revolutionize health care. Another way would be to use live cells prepared for stem cell xenotransplantation, binding them to the biodegradable biopolymers as scaffolds. Immunosuppression probably will be unnecessary, which is an advantage. These drugs are detrimental to the implanted fetal precursor stem cell xenotransplants. Regrettably, this line of research is not taken up to see if fetal precursor stem cells of animal origin can give better results than the approach using human-based cells.
SUMMARY
Despite our knowledge and understanding of stem cell biology and regenerative medicine, this exciting field is still in its infancy. I believe the experience gained and published by the classical cell therapists on cell xenotransplantation should be critically examined in order to achieve a better understanding of cell biology and stem cell transplantation. Mainstream stem cell researchers have acknowledged that there is a growing body of data in many tissue systems, indicating that stem cell function is critically influenced b extrinsic signals derived from the mesenchymal environment (internal body milieu). This is an area modulating stem cell behavior therapeutically.
The strength of the classical cell therapists has ben its holistic protocol, which includes a detailed preparation of the patient prior to therapy, with appropriate biomarkers t ensure that the patient is for this line of research. So currently, we have a situation where there research (embryonic, adult, inducible PSCs) expanding rate, thanks to funding, but still not having solutions on one side. On the other side, we have fetal precursor stem cell xenotransplantation, which is safe (if the stem cell transplants are manufactured by the stat of the art and by accredited laboratories in accordance with the US FDA and AAALAC) and with a long clinical experience in the treatment of currently untreatable diseases.
Unfortunately, there is not much fundamental research recently on cell therapy using cells from animal sources. It is hoped that the clinical experience accumulated over the eighty years in cell xenotransplantation will be used to generate many research hypotheses that will enable translational scientists to provide us with a deeper understanding of how, why, when, and in what clinical situation based therapy is available, patients desperate in need for live-cell therapy should be given the treatment.
In the future, regenerative medicine will include replacing nonfunctioning organs and tissues of the human body by artificial means as it will never be possible to meet the need for matching organs such as kidney, liver, heart, or other human tissues or organs to treat patients. This is going to be a very important field. Regeneration and reconstructive medicine are important milestones in medicine that will bring definitive benefits to the quality of life of patients.
References
Dr. Abdul Halim Abdul Jalil
Dr. K. Takahasi, S. Yamanaka
Dr. Paolo De Coppi, Dr. Anthony Atala
Dr. Majezan Ya'acob
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