Introduction to Regenerative Medicine

Chapter Two

Introduction to Regenerative Medicine 

Regenerative medicine and therapy is an innovative concept described through a new research field and represents a unique approach towards the goal of regenerating functional tissues and organs. On the occasion of the publishing of Regenerative Medicin and Therapy, I would like to share with readers the insights into the genesis, current research status and exciting advances in this critically important realm of health sciences --- Regenerative Medicine.

I: Consideration of Scientific Paradigms and Research Reasoning from the Viewpoint of Foundation and Development of Medical Science Systems.

Medical historians today are fortunate to be able to scan, across thousands of years, the extensive research focusing on human health problems and related therapies which have evolved today into the modern disciplines of life science and medicine.  

During the development of these modern disciplines, certain questions have consistently arisen in the minds of generations of researchers including: “What are the advantages and disadvantages of a current medical system?” “What medical practice will be adopted in the future that is most advantageous for human physiology and health?” and “Is it possible for the average human being to attain one hundred years of age and still be in good health?” The question as to what the future of medicine will reveal has always teased men and women in the health sciences. As early as 2,000 years ago, both eastern and western medicine originally arose from an apprenticeship with nature and natural phenomena. Everyone attempted to harness nature’s secrets to solve the health problems of their time.  The first written documentation on traditional Chinese medicine is the Huang-Di Nei-Jing or Yellow Emperor's Cannon of Internal Medicine (http://www.hungkuen.net/tcm-history.htm) that was finished during the Spring and Autumn Warring States Period (between 800 B.C. and 200 B.C.).  This documentation represents the development of medicine away from sorcery and en route to being used as the foundation of Chinese medicine. Shen Nong (3493B.C.) hailed as the "Divine Cultivator" tested myriad herbs, and in so doing gave birth to the art of medicine.  Hua Tuo (110-207 A.D) was the most famous doctor in ancient China who developed the use of Mafei San (surgical anaesthesia) a good 1,600-1,700 years before western doctors learned about ether and other chemical or pharmacological anesthetic agents. These and other great achievements supported the foundation of Chinese medicine with its comprehensive and systematic gifts which include modern day’s internal medicine and surgery.  

Ancient Greece and Rome dominated the empiricism of the ancient west. At around 6 B.C., Alcaemon (http://emuseum.mankato.msus.edu/prehistory/aegean/culture/greekmedicine.html), from ancient Greece, performed human autopsies and concluded that the brain was the organ of thought and sense. By the 5th century BC, Hippocrates, father of modern western medicine, after studying the conditions of dying patients, (http://www.cpus.gov.cn/kxrw/index.asp?rw=419&jiang=0), articulated the elaborate general doctrine that all of the Four Humors,  phlegm, blood, yellow bile and black bile, had to be in correct proportion to one another for health to result.  (http://www.med.virginia.edu/hs-library/historical/antiqua/textn.htm).  Almost the same time, Aristotle (http://www-groups.dcs.st-and.ac.uk/~history/Mathematicians/ Aristotle.html) the student of Plato, pushed back the frontiers of knowledge and superceded his teacher by proposing that the earth was composed of the four elements: earth, water, air and fire.  (http://galileo.imss.firenze.it/museo/b/earisto.html). With about 2500 years of development, there came into being two academic systems: eastern medicine and western medicine.  Eastern medicine, which originated from ancient Chinese medicine, has brought tons of benefits and contributions to human health by providing treatments based on the plain philosophy and holism, while western medicine experienced two periods: one during the warring period of ancient Egypt and ancient Rome when the massive wounded were treated, which brought morphologic research from anatomy to applied surgery, and the other during the Renaissance when medicinal chemistry was developed based on the alchemy, thereby resulting in the rudiments of modern western medicine and surgery.

Historically, both eastern and western medicine have continuously integrated modern scientific discoveries into their medical treatments and thus continued to develop. However, historians might also question what kind of significant benefits, whether in Chinese or western medicine, these discoveries have played in promoting human health and in effectively treating diseases. Let me share with you an image that concerns me. Imagine a modern, well-educated medical doctor holding a knife in his left hand and a pharmaceutical drug, a cellular poison, in his right. Now he suggests to the patient: “I will use the knife to excise your injured organ to cure disease and save your life and then I will use the ‘poison’ to cure the disease. Is that OK?” You see, combating poison with poison, is the paradigm which we were taught by the older generations of doctors. And because no one offered a more reasonable option, western drugs today are made primarily of chemical toxins which are incompatible with life and which, not surprisingly, when applied to diseased human beings, inevitably have deleterious side effects on health. Therefore, it is not an unjust comparison to liken western drugs to poison when seen in the context of the rule of life or vitality.

For many centuries, medical professionals the world over have sought to reduce drug toxicity as much as possible while many governments have set up national drug control administrations to ensure drug safety for humans. However, no substantial and meaningful changes have been made to traditional medical system due to the inflexible concept of “poison” and, until now, due to the lack of effective nontoxic options for the treatment of disease. Where is the new medical system that conforms to the principles of human vitality? In which direction should the practice of human medicine go? Herein, I would like to share with devoted readers the exciting story of the establishment of regenerative medicine and therapy as well as our compelling research which supports this new paradigm shift towards a medicine which is in accordance with the laws of human health and wellness.

We inaugurated the research into the secrets of egenerative medicine and therapy in early 1980.  Although many difficult challenges fell before us since 1987 (the year we established out Research Center), our published research results demonstrate that we are presently amongst the leaders in this field. Back in 1989, I published research demonstrating the heretofore unthinkable result of scar-free healing of burns through the application of  regenerative cells. The clinical results were impressive and the pictures demonstrating irrefutable clinical effects (no scars) are available for the interested reader in The Chinese Journal of Burns, Wounds and Surface Ulcers.  

Subsequently, the work done by Dr. James A. Thomson and his colleagues from Wisconsin University in 1989 revealed that when cells were isolated directly from the inner cell mass of human embryos at the blastocyst stage and then cultured in vitro to produce a pluripotent stem cell line, they would then transform into many types of cells.  Thomson’s group believe that any cell from a fertilized egg, termed as “totipotent stem cells”, if placed into a woman's uterus, has the potential to develop into a fetus and then to form an entire viable organism.  Meanwhile, Dr. John Gearhart and his colleagues isolated pluripotent stem cells from fetal tissue of terminated pregnancies and confirmed Dr. Thomson’s results. Their work was published in Science and saluted as “the first breakthrough out of the ten big achievements in 1999”.  

This technological achievement triggered a burst of stem cell research and a whirlwind of ethical debate followed immediately by a drive for commercialization, some of which was quite unscrupulous. For example, a certain laboratory announced that they had created a human ear on the dorsum of rats. More stir! Not surprisingly though, on closer inspection, we learned that their statement was not actually true. In fact, the scientists in that laboratory did something different though not entirely insignificant. They managed to first make a human ear model scaffold using polyglycollic acid (macromolecule chemical material) and then, after placing this structure beneath the rat subcutis, cartilage cells cultured and proliferated within the said scaffold creating something that looked like an ear but was not one at all. Like a shadow perpetually attached to its master, commercialization is never far from the frontiers of science.

Imagination, while an important component of science, is only a distraction unless the rigor of the scientific method is also employed. No trickery is allowed. Unfortunately, such tricky performances -such as human ears on the back of mice- disturb the current field of stem cell research. Traditionally, Chinese scientists and doctors prefer to investigate principles from experimental results and holistic concepts in order to discover tri-dimensional development modes en route to comprehensive conclusions. In contrast, westerners are adept at imaging from scantling phenomenon, then designing several research directions for further exploration before finally attaining an answer. The Western mode of research necessarily requires adequate funding which seems to not be in short supply.  For example, a result that might require ten thousand dollars in China might require, in the West, a price of ten million dollars. Nonetheless, despite funding discrepancies, we are pleased to reveal that, though relatively underfunded, Chinese researchers have accomplished the clinical application of regenerative medicine while Western researches are still formulating strategies. This difference in degree of clinical success validates the eastern way of thinking about research, which produces empirically superior clinical results in an expeditious manner.

Our focus in this book will be to reveal that the clinical results springing from the research on burns wherein data suggest that most dry wounds heal with scar formation whereas most moist wounds heal with less scarring. While probing the mechanism of this superior healing over many years, we discovered one type of unknown cell that has a regenerative capacity which may play a significant role in this process. After years of basic research and clinical study, we found that the cells with regenerative potential turned out to be keratin 19 positive expressed epidermis stem cells which appear to be the primitive cells at the start of human embryonal development. Coincidently, this understanding shed a great light on the mystery of optimal physiological healing of deep burns by regeneration. Using wound repair as a model, we dynamically demonstrated that the process of skin regeneration and development can resemble embryonic tissue development. Based on the discovered skin regenerative law, we conducted experimental studies on the regeneration and repair of tissues and organs of mammals by creating a vital environment. I am now pleased to report that up to the present, we have had consistent success in repairing and regenerating 55 types of tissues and organs.  

II. Research Status of Stem Cell and Regenerative Medicine and Therapy from a Holistic Philosophy.

The “Healing” process can be observed to result in one or the other of two major sequelae—scarred and scar-free healing. Healing with scar formation is the result of aberrant and suboptimal physiological processes while scar-free healing is the result of healthy and appropriate physiological processes working in conjunction with the forces of regeneration. Mankind has always known this to be true but until now has failed to discover the dynamics behind the variable healing results. Certainly, if one could comprehend and reveal this mystery in order to apply it to medical fields, then the health of people the world over would be astonishingly enhanced.  Such a goal is worthy and, accordingly, that has been my focus and aspiration since I pioneered the science of regenerative medicine many years ago.

Let’s begin with definitions. The term “regeneration” implies that the human body can be stimulated to regenerate by itself through the use of its own potential but this stimulation requires both an appropriate trigger or promotion factor as well as an appropriate physiological environment. In fact, each tissue or organ, including epidermis, epithelium mucosa, vascular endotheliocyte as well as blood cell in human body is engaged in exactly this process all the time. Disease, therefore, can be understood to occur when the speed of repair is slower than the speed of injury. Until the present, a lot of pathological and physiological mechanisms remain obscure to those using the conventional paradigm. Therefore, in order to uncover the mystery of regeneration in human body, we must avoid the thoughts of traditional medical thought and instead utilize a new body of thought which we can apply to the observation and study of human physiology. This new body of science has led us to the field of regenerative medicine.

Our whole framework of Regenerative Medicine has epoch-making significance— diseases will be cured and the people’s health will be improved by the potentials whirling unharnessed within each human cell, tissue and organ.

In 1989, I announced the embryonic form of rgenerative mdicine. Today, 13 years later, American scientists are offering similar concepts, which they call “treatment of future regeneration”. Although they use the crude transplantation approach to accomplish the renaissance of organs, nonetheless, they do make use of the human body’s regenerative potential. Our schematic thoughts of rgenerative mdicine focused on the in vivo and in situ organ regeneration, it’s the life regeneration combined with human physiological activities. While already bearing clinical fruit, I believe our system of rgenerative mdicine will continue to develop and mature as we complete our research. Until now, our ideas are the most advanced and, to our knowledge, are the only ones whose efficacy is confirmed by clinic practice. Because of this, we submit our proof of rgenerative medicine as a scientific conclusion, not a hypothesis.   

On February 26^th 2002, we attended the Stem Cells Regenerative Medicine Conference held in New Jersey. Participants had intense debates focusing on areas of stem cell research which we had already finished and where we had a lot great achievements.   

Though some scientists announced their success in reconstituting “bone” or “heart”, experts and investors alike declared that they only wanted to see some real results.  This is in accordance with the principles of science where results are what counts. Results are more important than theories. Accomplished research which springs from the solid foundation of truthful thoughts is the path to progress and innovation.

Physiological tissue repair and functional organ regeneration through cultivation in deep burn management has been demonstrated in our research results. The repair and promotion of mucosal tissue regeneration in the gastrointestinal tract is of interest but will not be detailed at this time. Stem cell research, which is widely known to the public, mainly refers to conventional hematopoietic stem cells.  However, great debates are continuing over whether hematopooietic stem cells are the appropriate ones to use because these cells are immature. What is stem cell? A stem cell is an undifferentiated or partly differentiated cell with the capacity of transforming into “mediate cells” with structure and function of tissues and organs.  Stem cells are similar to tumor cells as regards their proliferative capacity, but the former constitute normal tissues and organs ultimately, while the later forms tumors. The unique characteristic of stem cells is that they can develop into fully functional organs.  

In the February conference, I presented our research results. Comparisons were made to current American advances in this field. Though we found that histiocytes of each tissue and organ have the potential to regenerate, the challenging problem to doctors and researchers is how to maintain and induce the regeneration of these cells.  In our burns treatment, we have worked out a great success.  We use moist-exposed burns ointment (MEBO) to treat deep second-degree burns and by creating a physiological environment and adding life-regenerative substances, we facilitate healing without scar formation.  Information about regenerating skin subsequent to second- and third-degree burns wounds will be discussed later.  This innovative burn medical therapy (MEBT) is not only applicable to treating burn injuries, but also to the replacement and reformation of human skin – an innovation from which everyone may benefit.  

Entering into 21^st century, almost every doctor may question which innovative therapy is most promising for modern medicine. Many life scientists and physicians have turned their attention to stem cell research. There are various research approaches to the study of stem cell potential. Foremost of these is embryonic stem cells, hematopoietic stem cells and adult stem cells. No matter which kind of stem cell, the dream of renewing the human body’s physiological function lies in the stem cells research in vivo and in situ.  The law of in situ regeneration is the only one with any value of medical application.  

III. Discussion of the Future of Regenerative Medicine and Therapy Based on the Results of Multi-organ Regeneration Research.

Despite continuous progresses in science and technology, few attempts have been made to successfully develop functional tissue or organs from human cells. The exception is our embryology study and our work on the adult stem cells in vivo and in situ.  Almost one decade ago, American researchers tried to establish a new life science system using various approaches and electronic technologies, but ended up only describing an ideal blueprint for the human genome. However, without sufficient understanding about cells, the genomic research that only focuses on life substance within the cell is of little applicable value since genes play their roles under the assistance of the function of cells.  It is true that genomic research is very important in the life science, but such research will accomplish nothing if it is removed from cellular biochemistry and cytology.  While an important approach to life science research, gene technology proves inadequate to solve any health problem or cure any disease unless combined with appropriate use of cytology focused on harnessing the function of the cell, life’s smallest unit.

Stem cell research and its application is another hot topic in life science apart from genomic. According to current reports from over the world, the most advanced stem cell research is the isolation and culture of stem cell in vitro before transplanting “tissue” which has been engineered (example: epithelium tissues and cartilage transplanted into the patients).  However, a challenging problem that remains unsolved is how to maintain continuous proliferation of stem cells in vitro. It is well known that the environment in vitro does not completely meet the actual physiological requirements as that in vivo and in situ. The inadequate transmission of information and suboptimal regulation between