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The history of fetal precursor cell transplantation is actually a history of fetal precursor cell xeno-transplantation.

It was not until the late 70-ies of the last century when human fetal tissue transplantation (‘allotransplantation’) began in the U.S.S.R. and from there spread into some other communist countries, i.e. Yugoslavia, Hungary, German Democratic Republic, Peoples’ Republic of China.

In the late 80-ies Hana Biologicals, a public corporation based in Alameda, California, began procurement of human fetal tissue transplants in cooperation with a human fetus collection company in Philadelphia, PA. After U.S. FDA approved clinical trial of treatment of type 1 diabetes mellitus by transplantation of cells produced by Hana Biologicals failed, all cell transplantation activity ceased in the U.S. until 2001.

This idea was born a long time ago.

Papyrus of Eber - 3,000 B.C. - described preparation of medications from animal organs.

Susruta1,400 B.C. (Mesopotamia, today Irak) – prescribed ingestion of sex glands of young tigers as treatment of impotence.

Hippocrates470 – 410 B.C. – carried out transplantation of frog skin to treat man.

Aristoteles384 – 322 B.C., and Plinius the Elder -23 – 79 A.D., described preparation and use of animal and human organ extracts for human treatment.

Paracelsus (Theofrastus Bombastus of Hohenheim) – 1493 – 1541 - wrote in his book: ‘Heart heals heart, kidneys heal kidneys’ and “Like heals like”, i.e. he discovered organospecificity, one of the scientific principles of modern fetal precursor cell transplantation..

Hooke1663 – discovered a cell.

Schleiden1838 – discovered that cells are the structural basis of all plants.

Schwann1839 – discovered that cells are the structural basis of all animals, not only of plants.

Hunter1771 - and Berthold1849 – proved substitution effect of implanted sex glands on a castrated cock.

Brown-Sequard1889 – presented to the fellow members of French Academy of Sciences report on self-treatment by implantation of rooster sex glands for revitalization (as an elderly widower he re-married a much younger woman that caused problems which he, the most famous physiologist of his era, resolved). This was the first documented case of cell xeno-transplantation in the history of medicine. Immunosuppression was unknown then.

Virchow1821 –1902, father of modern pathology, stated that “all life stems from cells”, and that “there is no life without cells”. Or, in other words, that ‘cells are bearers of all life’.

Carell1873 – 1944, father of cell biology, (first U.S. Nobel prize winner, in 1912, for discovering technique of surgical suture of blood vessels), succeded in keeping a tissue culture of chick embryo cardiomyoblasts alive indefinitely, as long as the tissue culture medium was replenished at regular intervals by another containing a small amount of the same embryonic cells. Actually his tissue culture was allowed to expire after 34 years.

Cushing 1869 – 1939, one of the fathers of neurosurgery, was also the most important endocrinologist of all times due to his pioneering research on pituitary hormones and their relations to hormones of hypothalamus, adrenals, and other peripheral endocrine organs. Niehans credited Cushing with some of his ideas that were included in the concept of cell therapy / cell transplantation.

Landsteiner1900 – discovered blood groups, thus making blood transfusion safe, without immunosuppression. Blood transfusion was the first widely used method of cell transplantation in clinical practice.

Kuttner1912 - succesfully transplanted human adult thyroid tissue to another patient after thyroidectomy. Immunosuppression was unknown at that time.

Voronoff1910 – began to widely use xeno-transplantation in clinical practice. His research on transplantation of animal (monkey) testes to aging men caught attention of media and brought him notoriety. Unfortunately monkeys are carriers of syphilis (which is harmless to them) and thus his patients acquired a dangerous disease, for which there was no treatment at that time. Today by following U.S. FDA and WHO rules on manufacturing xeno-transplants this kind of disaster would be impossible. No immunosuppression was used then.

Niehans1982 – 1971 – doctor of Lutheran theology and doctor of medicine, decorated hero of WW1 and WW2, a member of Papal Academy of Sciences, an illegitimate child of the last German Kaiser, developed between 1920 and 1931 ‘cell therapy’* that was defined by him as a transplantation of freshly obtained animal fetal tissue fragments of various, in principle all, organs for treatment of man.

In 1927 he succesfully used implantation of fresh calf pituitary tissue fragments for treatment of pituitary dwarfs. In 1929 he treated patients with chronic polyarthritis by a similar method with success.

In 1931 he was asked to save life of a woman dying of tetany due to accidental removal of all parathyroid glands during total thyroidectomy by a famous surgeon. As there was no time even for the usual minor implantation surgery, P. Niehans took surgical scissors and chopped down the animal parathyroid glands obtained from the slaughterhouse so that it would pass through an injection needle, and implanted the tissue fragments thus obtained with syringe and large-bore needle. The patient survived and lived for another 21 years. Thereby ‘cell therapy’ was born, created in a life or death situation, without any research or scientific discussions. This genius clinician treated more VIP’s of our world than any other physician alive or dead. He did not use any immunosuppression.

In 1954, during ‘Therapy Week’ in Karlsruhe, Germany, around 5,000 physicians packed the auditorium, standing in vestibule and halls, in order to listen to his lectures. As a result of his teachings and that of his most glorious followers: SCHMID, STEIN, SCHMIDT, KMENT, NEUMANN, HOEPKE, v. LANGENDORFF, BERNHARD, LETTRE, LANDSBERGER, ANDRES, WOLF, GIANOLI, CAMERER, and others, as many as 5 million patients were treated by cell therapy ( more than 4 million of that in Germany), of which around one million was treated by live cell transplants. Afterward the definition of cell therapy was enlarged to include the use of preserved cells for treatment.

In 50-ies P. Niehans received one night visitors from an insulin-maker Eli Lilly Co. with a check for U.S. $ 1,000,000,- to induce him to stop his attempts to find a treatment of diabetes mellitus by cell therapy. (To find a treatment for diabetes mellitus and cancer by cell therapy was his lifelong obsession.) After he refused, pharmaceutical industry began to systematically attack cell therapy. After 1956 all publications about cell therapy /cell transplantation stopped in U.S., and from that time no U.S. medical school library kept any German medical journals known to publish articles about cell therapy / cell transplantation, or books.

In 1987 German government banned the sale of preserved celltherapeutica in pharmacies, but when it attempted to ban cell therapy altogether in 1997, i.e. fresh cell therapy / cell transplantation, it failed. German Supreme Court ruled on February 16, 2000, that fresh cell therapy / cell transplantation is safe, and overturned the attempted ban.. This decision means that cell therapy has continued to be permitted in Germany and thereby in the entire European Union.

Filatow – 1875 – 1956 – father of transplantation of cornea, while developing his method came in 1933 across an idea to use implantation of fragments of human placenta to improve results of corneal transplantation. Implantation of human placental fragments became the most popular biological therapeutic method to-date, worldwide, known under numerous names, usually that of the clinic owner. No immunosuppression has ever been used.

Kasakow – in 1925, based on the method of Tuchnow, developed treatment by cell hydrolysates, which became well known in USSR. Subsequent to the death of the deputy chief of NKVD (predecessor of KGB), allegedly as a result of such therapy, Kasakow was sentenced to death, his governmental institute eliminated and all writings locked up for generations by KGB in a library of banned literature, until partially discovered by BCRO in 1993.

Shumakow – 1979 – published in a peer reviewed journal about the success of cell transplants prepared by tissue culture in the treatment of a female with severe complications of insulin dependent diabetes mellitus, without immunosuppression; the patient was well for 21 years without any additional cell transplantation.

Bio-Cellular Research Organization (BCRO) – subsequent to U.S. FDA issuing regulations about preparation of cell, tissue and organ xeno-transplantations in September 1996, BCRO completed the development of its method of manufacturing of cell transplants of animal fetal origin, and after filing U.S. Patent application in 1998, began preparation of fetal precursor cell transplants individually for each patient in July 1998.

BCRO has not discovered a procedure of fetal precursor cell transplantation, it found a method to prepare fetal precursor cell xeno-transplants of any of around 220 kinds of cells that all mammals are made of, for clinical use, that can be implanted with ‘state-of-art’ safety, and without immunosuppression. (The author has been a managing director of BCRO since its inception in 1989.)

NOTES: Anglophone medical literature uses the term ‘cell transplantation’, while German literature has used the term ‘cell therapy’ (‘zellentherapie’) for implantation of tissue fragments of animal fetal origin. German law does not recognize the term ‘cell transplantation’ and U.S. FDA banned ‘cell therapy’ sometimes in 1956.

There is a discrepancy between terms ‘cell therapy’ and ‘cell transplantation’ when it comes to an implantation of tissue fragments of animal fetal origin. ‘Cell transplantation’ includes only ‘fresh cell therapy’ as in the original definition of Niehans, but not the use of preserved cells (preservation by lyophilization causes cells to lose cell membrane and thereby they are no longer live, preservation by freezing - as it used to be done in those days – leads to death of 85 – 95% of cells, mostly during thawing process). Today in German ‘cell therapy’ (‘zellentherapie’) means use of animal preserved cells or cellular material for treatment, while ‘fresh cell therapy’ (‘frischzellentherapie’) means the use of freshly obtained animal fetal tissue fragments of animal origin for therapeutic implantation.

Fetal precursor cell transplantation was introduced into clinical practice in 1931 and has historically preceded organ transplantation by several decades. It shall dominate the medicine of 21st century.

Brief summary of author’s experience with fetal precursor cell allo- and xeno-transplantation.

It all began , after post-mortem pledge to his father in 1976, who died by a horrible death from complications of diabetes mellitus, to search for therapy/ies that would have saved his life, at first by the study of German and Soviet information bases of cell transplantation, and the by close cooperation with the leaders in this field in Germany between 1981 - 1997, and finally by organizing a major clinical research work of International Institute of Biological Medicine (IIBM), a USSR/Russian corporation, created in 1991 by Bio-Cellular Research Organization (BCRO), as 51% shareholder, together with a division of the USSR Ministry of Health Care, in the field of human fetal precursor cell transplantation. After the fall of USSR in December 1991, 49% of shares of IIBM were taken over by the Ministry of Health and Health Care of Russian Federation. In 1993, the work of BCRO/IIBM in the treatment of patients with complications of diabetes mellitus attracted the attention of Sansum Medical Research Foundation, Santa Barbara, Calif., (‘Sansum’), that organized in that year the first U.S. clinical trial in the use of the combined fetal precursor allo-/ xeno- cell transplantation for a treatment of complications of IDDM, a cooperation between BCRO and Sansum. (Dr. Sansum was the first U.S. physician to use insulin in his medical practice.)

On August 1, 1993, a total of 24 U.S. patients with complications of IDDM, predominanly of retinopathy and nephropathy, were treated by IIBM in the clinical facility of Sansum in Santa Barbara, Calif. A manuscript describing the positive clinical results of this trial was submitted for publication to ‘Transplantation’ by medical teams of Sansum and IIBM. It reported on the treatment of 24 patients with Type 1 diabetes mellitus with retinopathy, nephropathy or both, with duration of diabetes of 21±7 years. During 12 months’ follow-up the insulin requirement was significantly reduced by 21±8% (p=0.0260), systolic blood pressure was significantly reduced from 120±17 to 111±13 (p=0.012), and diastolic blood pressure from 78±8 to 72±8 (p=0.005). Total body weights were reduced from 153±30 to 150±28 (p=0.189), and HbA1c from 7.1±1.4 to 6.8±1.2 (p=0.222). Plasma levels of C-peptide increased from 0.06 ng/ml before treatment to 0.186 ng/ml one year later (p=0.01). There was no further progression of retinopathy and nephropathy in any of the 24 patients during the one year follow-up. One female patient became pregnant during this time. VI.BIBLIOGRAPHY [115]

U.S. company, created by personnel of Sansum, organized a continuation of these clinical trials in 1995 at Los Gatos Community Hospital, Los Gatos, Calif. VI.BIBLIOGRAPHY [113]. On three different occasions in 1995, altogether 32 U.S. patients with complications of IDDM (n=27) and NIDDM (n=5) were treated by IIBM in the clinic facilities of Los Gatos Community Hospital, again by combined fetal precursor allo- / xeno- cell transplantation, as at Sansum in 1993. During 12 months’ follow-up insulin requirement was significantly reduced by 41±8% (p=0.001), blood glucose levels stabilized from 229±44 mg/dl to 104±21 mg/dl, and plasma levels of C-peptide increased significantly from 0.09 ng/ml to 0.49 ng/ml (p=0.001). Diabetic complications of every patient remained stable, the creatinine clearance of one patient with diabetic nephropathy improved from 39 ml/min to 58 ml/min. (112) The islet cell transplants used in the treatment of all 56 U.S. patients were prepared by IIBM from fetal / newborn rabbits.

Besides that BCRO stem cell transplants have been used in Germany, Italy, Czech Republic, Slovakia, Mexico, Switzerland, Thailand, South Africa, Indonesia, Peoples’ Republic of China, Hong Kong, Macau, India, Malaysia, Australia, Panama, Austria, Nigeria, Singapore, while that of IIBM in the Emirates and Qatar.

Besides the patients treatment, the author has conducted his all day long seminars repeatedly in all major cities of all of the above countries, plus that of Kuwait, Egypt, Jordan, Turkey, Cambodia, South Korea, Taiwan, Republic of Georgia, Rumania, Yugoslavia, Bashkiria.

This method of treatment has been around for over 90 years in several different countries: Germany, Switzerland, France, Italy, Spain, Austria, USSR, etc. Political, philosophical, professional, language, and other barriers have caused the absence of professional and scientific communication in this new field of medicine between two pioneering countries: Germany and U.S.S.R. The author succeeded in overcoming this barrier and accomplished a symbiosis between 'zellentherapie' and 'kletochnaia terapia. under 'BCRO fetal precursor cell transplantation'.

Germany has been the only country in the West where various methods of cell therapy / transplantation have been widely used since 50-ies. The form of this treatment known as ‘fresh cell therapy’ (’frischzellentherapie’), has been used to this date. In February 2000 the Bundesverfassungsgericht (‘German Supreme Court’) in Karlsruhe, case number: 1 BvR 420/97, ruled positively about a continuous approval of this therapeutic method. Since over 800,000 patients have been treated by fresh cell therapy in Germany during the past 65 years, this was quite an impressive statement. (Another more than 4 million patients have been treated during this time by frozen and lyophilized ‘cell-therapeutica’, registered in West Germany until 1987.)

In 1984 the Ministry of Health of U.S.S.R. issued ‘Recommendations on the Method’ (the same type of document as ‘U.S. FDA regulations’) dealing with cell transplantation that amounted to the official approval of this treatment. VI.BIBLIOGRAPHY [76] It confirmed a completion of a major pre-clinical and clinical research in this field in the U.S.S.R.VI.BIBLIOGRAPHY [78], which led to the succeful treatment of a patient with complications of IDDM (by fetal precursor allo-transplantation), already in 1979, and thereafter thousands of other diabetics and patients suffering of other untreatable diseases.

Since the Ministry of Health of U.S.S.R. put its Research Institute of Transplantology and Artificial Organs of the Ministry of Health of U.S.S.R. (‘RITAOMH’) in charge of this work, and the transplantologists, ‘big surgeons’, were much more interested in organ transplantation than in ‘just simple injections of cells’, the method did not attract much attention within the socialized health care system. Only after IIBM became active in the new Russian Federation in 1991, the fetal cell transplantation became known as a therapeutic method also outside of the ‘Fourth Department’, health care system for ‘nomenclatura’ (‘apparatchiks’), and the ‘Third Department’, health care system in the military , and was included in the list of approved therapies by the Ministry of Health Care of Russian Federation, health care system for the general public, and received a governmental code.

By the decree of the Minister of Health of Russian Federation of November 1994 it is now a duty of a diabetologist in Russia to refer a diabetic patient for cell transplantation, if indicated. VI.BIBLIOGRAPHY [77]

By the time of its first international symposium in December 1995, in Moscow, IIBM treated by fetal precursor cell allo- and xeno-transplantation around 3,000 private patients with a variety of diseases, besides many thousands treated under various clinical research projects. Thus in the span of 4 years (1993 - 6) IIBM treated the same number of patients as 12 top Soviet research institutes since 1979.

The major contribution of IIBM was its never presented work, carried out together with the staff of RITAOMH, in which the clinical results of cell transplantation by fetal precursor allo- and xeno-transplants were compared. This study proved the overall superiority of fetal cell xeno-transplantation. The main reason was a much better quality of the animal (rabbit) source of cell transplants. While the animal (rabbit) material could be obtained always (!) perfectly fresh, i.e. cells were 100% live when planted onto the tissue culture medium, the same could hardly ever be stated about human fetal material, where for obvious reasons there was always a delay between the time of death and the dissection of human fetal cadaver, often quite substantial, so that the viability of cells at the time of their planting onto the tissue culture medium was questionable.

For clarification, ultimately there were 12 major medical research institutes in 5 different republics of U.S.S.R. involved in cell transplantation. It should be noted that medical science was organized in U.S.S.R. under a ‘pyramidal principle’, i.e. in each field of science there was a central U.S.S.R. institute in charge for the whole country, for example RITAOMH in transplantology, and then there were central institutes in each field of medical science in charge in each of 15 republics of U.S.S.R.

Although RITAOMH was in overall control in the transplantology, the main institutes of each Republic had a latitude in their actions. Initially, some of them were carrying out only fetal precursor cell allo-transplantation while others only fetal cell xeno-transplantation, with bovine or porcine fetuses as sources of transplants, and some of these institutes carried out both fetal precursor cell allo- and xeno-transplantation.

Ultimately fetal precursor cell allo-transplantation was abandoned by all of them in favor of fetal cell xeno-transplantation. Among 12 research institutes involved in cell transplantation, only RITAOMH switched from bovine and porcine fetuses to the rabbit fetuses as a source of cell xeno-transplants, and that began in 1987. The change of the of source of cell xeno-transplants coincided with the fall of communism and of the U.S.S.R., which caused a major breakdown of Russian medical science, medical industry, and health care, with a subsequent decrease of medical publication activity as well.

As a result, there is much less published material about the cell xeno-transplantation with fetal and newborn rabbits as a source of transplants, as compared with bovine and porcine fetuses. In ‘Bibliography’ are included also dissertations for the degree of ‘Candidate of Medical Sciences’ (‘Ph.D.’), and for the degree ‘Doctor od Medical Sciences’, mandatory for all future professors, carried out under the roof of RITAOMH, summaries of lectures from the various ‘All-U.S.S.R.’ congresses on cell, tissue and organ transplantation: 10th All-U.S.S.R. Symposium on Organ Transplantation, 1985, in Kiev (now Ukraine), 4th Congress of Ukrainian Endocrinologists, 1987, in Kiev, Symposium on Transplantologic Methods of Treatment of Diabetes Mellitus, 1988, in Riga (now Latvia), 3rd All-U.S.S.R.Congress of Endocrinology, 1989, in Tashkent (now Uzbekistan), 11th All-U.S.S.R. Symposium on Organ Transplantation, 1990, in Lvov, (now Ukraine), and from the symposiums at RITAOMH in Moscow, as well as from the yearly International Symposia ‘Transplantation of Endocrine Pancreas’, organized by the Institute for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center, Belgrade, Yugoslavia.

Prior to being invited to U.S.S.R. by the last USSR Minister of Health, Prof.Dr. Chazov, Nobel Peace Prize winner, in June 1990, the author and BCRO began its work in the field of cell transplantation in Eastern Europe in September 1988 in Yugoslavia. For pragmatic reasons Yugoslav colleagues decided to base the project in the Medical School in Sarajevo, today Bosnia/Hercegovina, and that decision proved unfortunate since: in early 1990 the project was stopped by civil war, and so the project moved to U.S.S.R.