Treatment of Incurable and No Longer Treatable Diseases of Central Nervous System by

BCRO Fetal Cell Transplantation

E. Michael Molnar, M.D., M.S.

History (1)Mexico City 1980’s: neurotransplantation for advanced Parkinson’s disease, a new vista in neurology, ‘no hope’ medical specialty due to lack of tx for majority of CNS diseases, soon taken up by Sweden, U.S.A., West Germany.Success rate of neurotransplantation in animal experiment over 95%, while in clinical practice using human fetal cell transplantation via surgery, only 2 – 3%.Our International Institute of Biological Medicine (51% Bio-Cellular Research Organization, 49% USSR Ministry of Health), launched in Moscow in 1990, carried out extensive research to find reasons for such major failure. Our initial rules:1/ in order to establish synaptic connections with neurons of the host it is mandatory to transplant cells with known and pre-determined properties: human fetal brain cells are not the sole cells capable to do that, animal are better; 2/ transplanted cells must be highly metabolically active: human fetal brain cells cannot fulfill such requirement unless combined with other kinds of cells; 3/ transplanted cells must be genetically strongly pre-set in their direction of differentiation, and be independent of environmental influences: human embryonic/fetal cells from the anterior portion of mesencephalon will not work because they are undifferentiated/pluripotent.

History (2)Experiments with xeno-neuro-transplantation between non-vertebrates and vertebrates, and xeno- and allo-transplantation between various species of mammals showed that survival of xeno-transplants in the host brain is 3x longer than of allo-transplants. Xeno-neurotransplantation between genetically discordant species much more succesful than between genetically concordant species.Primordial brain cells of various genetic mutants of Drosophila melanogaster fulfilled the best the above three rules. Their neuro-transplantation into brain of various vertebrates, including all mammals, was unusually successful, i.e. their survival in the mammalian brain was minimally 2 – 3 months. They served as a stimulant for implanted human fetal brain cells, promoting their differentiation and vascularization AND growth of the host’s neuronal processes toward donor transplant AS WELL AS stimulation of circulation in adjacent host brain tissue.

50 parts of human fetal brain cells from ventral mesencephalon and basal ganglia with 1 part of primordial brain cells of a respective mutant of Drosophila were implanted into ventrolateral thalamic nuclei of Parkinson’s patients. - Clinical testing + autopsy of over 100 patients with GSW of brain in prolonged coma showed no untoward reaction toward such implantation.

History (3)Intrathecal implantation, intraventricular at first, then via the standard lumbar puncture, clinically tested over decades, has been used by us in all patients over the age of 12: it was proven nontraumatic by autopsies of patients in prolonged coma after GSW of brain, and complications-free. Success rate in hopeless Parkinson’s disease patients was 95% ( published in Bulletin 1994). One such patient died 8 months later of MI and autopsy proved the reason for success: use of the combination of brain cells from human fetus + mutant of Drosophila. Next, patients with prolonged coma not due to GSW of brain were treated without addition of brain cells of mutant of Drosophila. 28 years old female 16 days after anaphylactic shock and clinical death post I.M. Ampicillin woke up 18 hours after human fetal brain cortex cells transplantation. Then 45 years old male who lost BP during retinal detachment surgery, in coma for 25 days, woke up 2 days after transplantation of human fetal cells of brain cortex and medulla alba cerebri. (1994, the publication in ‘Meditsina’ of 14 case histories.) At First International Symposium in Moscow in December 1995 over 400 case histories of a fetal cell transplantation via lumbar puncture in patients with various incurable neurodegenerative diseases were given in 6 different reports. In 1980’s F. Schmid wrote on his succesful treatment of apallic syndrome in 33 children less than 12 years old without intrathecal implantation, not mandatory during the first 12 years of life since hemato-encephallic barrier not solid yet.

Neurodegenerative diseases (1)

The existing treatments of all degenerative diseases suffer from one common problem: no attempt at regeneration of degenerating cells of diseased organs or tissues is ever made by current medicine. The sole treatment capable of direct stimulation of regeneration of degenerating organs is fetal precursor cell transplantation. That applies primarily to the neurodegenerative diseases.

Ability to accept an information from one neuron and pass it to another one requires a participation of membrane receptors activated by neurotransmitters. When axon is interrupted, its distal part dies, i.e. Wallerian axonal degeneration. Axons of central neurons do not grow back, they undergo apoptosis. The same happens when retrograde axonal transport is interrupted in the intact axon. As compared with central neurons in peripheral axons the proximal stump can grow back.

Interruption of axon will not only cause death of primarily damaged neuron but also the apoptosis of target cell, i.e. ‘anterograde transneuronal degeneration’ and sometimes also the apoptosis of cells innervating the damaged neuron, i.e. ‘retrograde transneuronal degeneration’.

Neurodegenerative diseases (2)

Due to ‘demyelination’ of nerve fibers more electric energy is required for reversal of polarization of internodium. If the electric current produced at internodium 1 is not sufficient to depolarize the next internodium 2, transmission of the stimulus is interrupted or slowed down. The rate of slow-down can vary in different nerve fibers, thereby time dispersal of signal ensues.

The damaged locus along the demyelinated nerve fiber can spontaneously generate action potential, with jumping onto the neighboring fibers, or with retrograde transmission. That leads to ‘shorting’ so typical of MS.

BCRO fetal cell transplantation as treatment for neurodegenerative diseases must focus – besides CNS - on the treatment of GI system and metabolism.

Classification of Neurodegenerative diseases (1)

A. Leukodystrophies:- Metachromatic leukodystrophy (D=dementia);- Globoid leukodystrophy, M. Krabbe (D);- Cancellous marrow degeneration, M. Canavan (D);- Sudanophilic leukodystrophies, M. Pelizeus-Merzbacher (D)

B. Demyelinization diseases:- Diffuse sclerosis, Schilder encephalitis periaxialis;- Multiple sclerosis – no CNS fetal cell transplants to be used for tx!- Neuromyelitis optica, M. Devic

C. Spino-cerebellar degeneration:- Friedreich’s ataxia;- Ataxia-teleangiectasia, Louis-Bar syndrome (AR);- Abetalipoproteinemia, Acanthosis, Bassen-Kornzweig syndrome (D);- Refsum syndrome, AR;- Myoclonus encephalopathy, Kinsbourne syndrome

Neurodegenereative disease (2)

D. Cerebro-ocular degenerations:- Amaurotic idiocy, infantile form, Tay-Sachs disease (AR) (D);- late infantile form, Bielschowski disease;- juvenile form, Spielmeyer-Vogt disease;- Tapeto-retinal degeneration

E. Cerebro-cutaneous degenerations:- Tuberous sclerosis, Bourneville syndrome, AD;- Neurofibromatosis, v. Recklinghausen disease, AD; - Angiomatosis retinae et cerebelli, v. Hippel-Limdau disease

F. Spino-neuro-muscular degenerations:- Neural muscle atrophies: Wolrath-Kugelberg-Welander;- Werdning-Hoffman;- Charcot-Marie-Tooth;- Dejerine-Sottas- Progressive muscular dystrophies: Duchenne (XR);- Becker (XR);

Neurodegenereative disease (3)

- Myatonia congenita;- Thomsen myatonia;- Carnitine myopathy;- Myasthenia gravis;- Amyotrophic lateral sclerosis, Motor neuron disease;- Syringomyelia

G. Degeneration of basal ganglia:- Hepatolenticular degeneration, Wilson’s disease (AR) (D);- Dystonia musculorum deformans;- Huntington’s chorea; - Pigmentary degeneration of globus pallidus, Hallervorden-Spatz;- M. Parkinson

Cerebrovascular accident

Treatment of acute stage (only if caused by thrombus - 80% of cases):carotid incision, suctioning out thrombus, stent placement, immediate intra-carotid BCRO fetal cell transplantation.Treatment of subacute stage of any cause: after surgical removal of blood and blood clot from the cavity and early development of fibrous tissue, 4 – 6 weeks after the stroke, intrathecal implantation of BCRO fetal cell transplantation (via lumbar puncture).Treatment of chronic stage: 3 months after the stroke, by intrathecal implantation of BCRO fetal cell transplantation.

Recent and old spinal cord injuries

Recent injury: after emergency surgical repair + debridement, leave plastic catheters in the area of injury, and gently irrigate by BCRO fetal cell transplants Q 6 – 12 hours

Old injury: intrathecal implantation of BCRO fetal cell transplantation (via lumbar puncture) Q 6 months, with vigorous specialized rehabilitation.

Alzheimer disease (AD)Clinical triad starting at 20 – 30 years of age will cause a decrease of the entire spiritual performance level: 1/ organic brain disturbances: the cause of AD +2/ depression – as a symptom of the basic disease +3/ lack of vitality – main clinical feature of AD.Main goal of therapy: improvement in the lack of vitality.Kment: Revitalization is a preservation of vitality over an extended period of time, or the re-gaining of lost vitality in the later years of life – as objectively proven by statistically significant changes of several parameters of aging, that document an attainment of a younger biological age as compared with the chronological age.The earlier in the course of brain atrophy that BCRO fetal cell transplantation is carried out, the better will be the results. However, the improvement is possible also in the advanced stages of dementia, since BCRO FTC will increase the vitality even with an irrepairable loss of intellectual abilities.The problem is that psychometric diagnosis of dementia is not considered a sufficient proof of diagnosis of AD (as it was in USSR), only CT or MRI proof of brain atrophy is, which delays the therapy by BCRO FCT until the condition of the patient deteriorates too much. BCRO FCT is of value only when carried out at the stage of the disease when the patient ‘can no longer find his car keys’.

Scientific Basis of BCRO FCT(1)Precursor fetal cell transplants can be manufactured for clinical use from fetuses of any member of animal kingdom, from Homo Sapiens to fish.Body of humans and all mammals is built from 200 – 220 kinds of cells: ‘the building blocks’. All those 200 – 220 kinds of fetal cell transplants can be obtained from such sources.

Xeno-transplantation means the transplantation of live cells, tissues, or organs between the species, in human medicine from animals to humans.

Allo-transplantation means a transplantation within species, i.e. from a man to a man, or from horse to a horse, etc.

The described scientific data explain why it has been possible to implant cell transplants prepared from fetuses of rabbits, sheep, cattle, pigs, horses, and probably other mammals, in over 5 million documented patients over the past ~90 years, without any fatality or other serious consequences for individual patients or mankind.BCRO method has been preparing fetal cell transplants for human therapeutic use from rabbit fetuses originating from closed colony of rabbits – see WHO publications on closed colony rules.

Scientific Basis of BCRO FCT(2)Immunosuppression – to use it or not to use it with fetal cell transplantation – has been a subject of heated arguments among physicians practicing this field of medicine over the past 65+ years.

European physicians have never used immunosuppression after fetal cell transplantation, even when cells of animal fetal origin were used, because they observed in their clinical practice that- allergic reactions were infrequent (incidence less than 5%), - anaphylactic shock was extremely rare, and - allergic reactions never caused death of a patient(!).

This was established beyond any legal doubt by the investigation ordered by German Supreme Court in the case # 1 BvR 420/97.

Since in Europe over 5 million patients have been treated by various forms of cell transplantation, mostly of animal fetal origin, and none of them received immunosuppression after implantation, there was hardly any need to search for scientific proofs. “Res ipsa loquitur! (Facts speak for themselves!)”

Scientific Basis of BCRO FCT(3)There are many published medical reports, originating mostly from USSR official governmental research project on treatment of complications of type 1 diabetes mellitus by fetal cell transplantation on thousands of patients, showing that changes of laboratory parameters of the immune system function before and after fetal cell transplantation were minimal and statistically not significant.

Until we learn what life is, and many philosophers believe that it will never happen, and thus cannot explain many aspects of the function of living bodies, we have to be satisfied with the fact that implantation of ‘state-of-art’ fetal cell transplants does not cause untoward immune or allergic reactions.This controversy should have ended when BCRO presented the existence of its method to the U.S. FDA in 1999 in our four IND license applications.

BCRO method of preparation of fetal cell transplants individually for each patient incorporates all pertinent requirements of PHS Guidelines on Infectious Disease Issues in Xenotransplantation” of January 19, 2001 (Federal Register, Volume 66, Number 19, pages 8120 – 1), which is the final version of the same regulation issued initially as a ”Draft” on September 23, 1996 (available from Federal Register under 61FR49920).

Scientific Basis of BCRO FCT(4)On February 16, 2000, by its favorable ruling in the case 1 BvR 420/97, the German Supreme Court ('Bundesverfassungsgericht') re-affirmed that the permission for this type of treatment, in medical practice in Germany since early 1950-ies, has been continued.This decision of German Supreme Court, with a power of law, applies to all Member States of the European Union. Legally it is related to certain chapters of the 2001/83/EC European Community Council Directive, that in turn had become incorporated in national laws of all Member States of European Union, as mandated by Maastricht Treaty, specifically in Germany and Austria.BCRO method of preparation of animal precursor fetal cell transplants is in full compliance with the decision of the German Supreme Court in case of 1 BvR420/97, with EU Directives, as well as national laws of all Member States of European Union. Rabbit fetuses (and newborns) are the animal source for the preparation of fetal cell transplants by BCRO method, as has been the case for the past 18 years. Nowadays, when everyone panics about the 'Mad Cow Disease', it is important to stress that according to the world’s medical literature (and confirmed by the World Health Organization), no transmission of any viral disease has been known to occur between rabbit and man.

Scientific Basis of BCRO FCT(5)The natural barrier that has always existed in 'Nature' has been largely preventing transmission of infections between species. The more distant the species are, the stronger this barrier has been: this is the case between rabbit and man.Coming from a closed colony in existence for over 40 years, with documented lineages, having been bred and raised in captivity with a minimal exposure to vectors of infectious agents, the rabbit fetuses used for preparation of BCRO animal fetal cell transplants are and have been remarkably free of any disease.Besides that, rabbit is the sole laboratory animal in which no retroviruses have been identified yet, despite the fact that they should be present in all mammals.

It was stated by USSR Ministry of Health in their regulations issued already in 1984, that no immunosuppression is necessary when the cell transplants are prepared by their recommended method. Ample additional clinical evidence since then has further proven no clinically detectable immunogenicity after an implantation of BCRO type of fetal cell transplants.

No genetic manipulations are used in the preparation of fetal cell transplants by BCRO method.

Scientific Basis of BCRO FCT(6)Fetal cell transplantation (FCT) is a surgical procedure in which an implantation of fetal cells containing live tissue fragments, or cell clusters, of all organs and tissues, of human (allo-, or auto-) or animal (xeno-) origin, from fetal, or neonatal, stage of life, is carried out as therapy of diseases of humans and animals (but not from embryonic stage of life!!!). Fetal cell transplantation has been used successfully for ~90 years as treatment of many diseases for which modern medicine has had no therapy, or in which 'state-of-art' therapies stopped being effective. It is not a ’wonder drug’, or transplantation of some ’Mother-of-all-Cell’, i.e. universal stem cell, that cures everything.It has been the only known treatment for clinical situations when a repair or healing of any mal- (or non-) functioning cell type, of any tissue(s) and organ(s), damaged by disease, injury, or abnormal growth & development, has been necessary to save life of the patient or avoid serious disability. It is accomplished primarily by direct stimulation of regeneration of the patient’s own mal- (or non-) functioning cells of any such damaged tissue(s) or organ(s) or occasionally perhaps also by transplantation of new fetal cells to replace the function of those destroyed in the patient’s body, or already dead and replaced by scar tissue.

Scientific Basis of BCRO FCT(7)Without fetal cells we, or any other member of animal kingdom, cannot regenerate any cell type our body is made of, and death becomes inevitable. Without fetal cells there is no life for any multi-cellular member of animal kingdom, e.g. mammals and Homo Sapiens. The organisms of Homo sapiens and all mammals are built from the same ~200 to 220 cell types.Fetal cell xeno-transplantation in over 5 million patients during the period of 90+ years has not caused a single fatality, while there have been fatalities after human embryonic stem cell transplantation (only). Peer-reviewed medical journals and media reports have been failing to state that A/ the fact that embryonic stem cells are unusable for an actual patient treatment due to their oncogenicity has been known for over eight decades; B/ implantation of fetal precursor cells, several generations older than embryonic stem cells, have been used as a treatment for ~90 years; C/ fetal cells of animal fetal origin are equally effective, and safer, for the fetal cell transplantation treatment, and thereby all troubles with human embryonic and fetal cells can be avoided, i.e. moral, ethical, religious, etc.;D/ therapeutic use of cell transplants of animal fetal origin in several millions of patients over the last ~90 years has accumulated sufficient data to prove that fetal cell xeno-transplantation is not dangerous to an individual patient or to a mankind.

Scientific Basis of BCRO FCT(8)Let’s analyze the above four issues.A/ The fact that embryonic stem cells are unusable for an actual patient treatment due to their oncogenicity has been known for nine decades. Embryonic stem cells have unique capability to renew themselves, i.e. proliferate, and are pluri-potent, i.e. they have the potential to differentiate into any and all specialized cells of the body, with characteristic shape, and function. They remain in an undifferentiated state, uncommitted, until they get a signal to develop into one of specialized cell type of the body.But, embryonic stem cells apparently do not exist for any prolonged period of time in real life, i.e. in a living embryo, only in the laboratory dish.

The current optimism about embryonic stem cells is based on theoretical expectation of:

1/ their enormous ability to proliferate that makes them suitable for a factory level manufacturing of cells for therapeutic use. The unlimited potential of embryonic cells to proliferate sounds wonderful, but only until one does not recall that in cancer growth likewise one kind of cell stopped responding to the commands of the patient’s body, became independent, and became a ‘cell factory’.

Scientific Basis of BCRO FCT(9)2/ their capability to be manipulated into differentiation into any desired cell type to be used for cell transplantation treatment of patients. Manipulation of embryonic cells into differentiation, whereby precursors / progenitors of any and all specialized cell types of the body are created in a laboratory dish, is a wonderful idea, but also a formidable task, currently without a solution.

B/ Implantation of precursor fetal cells, several generations older than embryonic stem cells, have been used as a treatment for ~90 years. The precursor fetal cells used for implantation/transplantation are taken from fetus, at the stage of life when organogenesis is already in progress. Such precursor fetal cells are no longer pluri-potent and are committed to follow a predetermined path of differentiation along one lineage only, (in other words such cells are directed to produce cells that are specific for the kind of tissue where these fetal cells normally reside). They do follow the body commands.They retain the ability to proliferate without pre-determined differentiation for a long time, i.e. they are capable of long term self-renewal. This is because in fetal body the undifferentiated stem cells live in a millieu of various differentiated cells, and there is a lot of interaction between them, which is not the case when undifferentiated stem cells grow in tissue culture.

Scientific Basis of BCRO FCT(10)The stem cells cannot create in a laboratory conditions a three-dimensional body, or an organ, or even a tissue, so the question arises whether these cells grown in a laboratory dish are indeed the same stem cells that can be obtained from a fetus, where they have developed in a natural way, and where they created three-dimensional tissues and organs.It appears more physiological to take precursor fetal cells for transplantation from their natural environment in the fetal body, i.e. taking them together with other cells of the same ‘family’ in a cell-to-cell contact with each other, including cells of various generations of the same ‘family’, and then grow them in a primary tissue culture in order to have sufficient time for observation and safety tests, as well as for minimizing their immunogenicity so that they can be implanted without immunosuppression. The kind of environment in which stem cells are growing, i.e. either in tissue culture or in live human or animal body, makes a lot of difference when it comes to the direction of cell differentiation.Heavily promoted use of cell lines for preparation of stem cell transplants is a fabrication of scientific facts by peer reviewed medical journals and media. Cell transplants prepared from cell lines have never been used in the clinical practice for patient treatment. It has been ‘res ipsa loquitur’ for practicing cell transplantologists in Europe that cell transplants prepared from cell lines are not therapeutically effective(!).

Scientific Basis of BCRO FCT (11)The definition talks about an implantation of tissue fragments, or cell clusters, not of dispersed cells. Cell line means culturing of dispersed cells. While the growth of cells in an organ/ tissue culture is influenced by a variety of interrelationships between cells, such interactions are lacking in the cell culture of dispersed cells. Due to that the growth of dispersed cells in cell culture is difficult to impossible. Culturing of dispersed embryonic stem cells growing outside their natural environment is possible only on the cell matrices, currently known as ‘feeder layer’ of cells. The only other way is by culturing stem cells in their natural environment, inside of a living organism. In cell line of any cell type, as a result of living in artificial conditions of continuous cell culture, the cells are almost always abnormal. They are heteroploid, i.e. with an abnormal chromosome count, and due to the influence of selection so markedly changed, that they often cannot be recognized as derived from their tissue (or organ) of origin. In cell lines sex chromatin disappears, cell division runs without any controls, there is a decreased production of acids released into the culture medium, cell membranes of daughter cells are incomplete, there is a lack of histo-typical differentiation.

Scientific Basis of BCRO FCT(12)BCRO method of preparation of fetal cell transplants is based on the primary organ culture of tissue fragments, or cell clusters, and not on the primary cell culture of dispersed cells. It has been proven beyond doubt that cells in the tissue fragments communicate via contact, via soluble factors, and also via their electromagnetic fields. All such communications are missing in the cell culture of dispersed cells.Primary organ culture, as used in the BCRO method of preparation of fetal cell transplants, has a limited lifespan, determined by the lifespan of the tissue source of the culture, or of the donor. In primary organ cultures the cells maintain diploid set of chromosomes, typical for the normal somatic cells of the animal source of organ culture. They do not differ from the cells of the original organ or tissue planted on the organ culture neither structurally, nor biochemically. These cells grow in the same functional environment as when they were a part of an organism from which they were taken.Because of oncogenicity the scientists and clinical experts in the field of stem cell transplantation doubt that embryonic stem cell transplantation, human or animal, could ever be of any value in the treatment of human diseases. But even if it would be, there would be serious questions about what is really helping the patient: human embryonic stem cells or the feeder mouse cells without which the human embryonic stem cells cannot survive in laboratory dish

Scientific Basis of BCRO FCT(13)Is it just feeding or is it in reality a co-culture of human embryonic stem cells and mouse feeder cells? What is the outcome of such co-culturing is a question that needs an answer. In 2004, human embryonic stem cell transplants were classified by CBER of U.S. FDA as ‘stem cell xeno-transplants’ because they cannot be grown in a laboratory dish without a feeder layer of mouse cells, and thereby they were placed under U.S. FDA regulation “PHS Guidelines on Infectious Disease Issues in Xenotransplantation”of January 19, 2001. Another important issue is the comparison of the outcome of co-culture of feeder cells and embryonic stem cells in a Petri dish in laboratory conditions with the effect of implanted cells of animal fetal origin ’in situ’, when a ’co-culture’ takes place in the damaged organ of the human recipient / patient.

C/ Fetal cells of animal origin are equally effective, and safer, for the fetal cell transplantation treatment, and thereby all troubles with human embryonic and fetal cells can be avoided, i.e. moral, ethical, religious, etc.; ‘Res ipsa loquitur’ (‘matters speak for themselves’): there is no real difference between cell or tissue xeno-transplantation and allo-transplantation in clinical effectiveness, as was recognized by P. Niehans already in 30-ies of the 20th century and by all scientific leaders of German cell therapy in 50-ies.

Scientific Basis of BCRO FCT(14)For that reason there was no concern about inability to use human embryonic and fetal cells due to the prevailing ethical, moral, and religious, attitudes in western European countries. When you place side-by-side human and animal embryonic stem cells, or human and animal precursor fetal cells of the same type, you find out that they look alike, and even most of the available cell-surface markers are the same. The only way to tell the cells of one species from another is by their karyotype, the number and shape of chromosomes, (temporary structures created from the genetic material of each cell during one short phase of cell division).There is only one difference between Homo sapiens and the rest of mammals: the frontal lobe of the brain. The rest of the body of all members of animal kingdom, including man, is the same on cytological level.Human cell transplantation, i.e. allo-transplantation, is not, and will not, be better than, or superior to, cell xeno-transplantation as the therapeutic tool in human medicine, until the quality of fetal cell allo-transplants matches that of fetal cell xeno-transplants. That would happen only if human beings would be kept in closed colonies, and euthanasia would be permitted in the preparation of human fetal cell transplants.

Scientific Basis of BCRO FCT(15)The main point is a much better quality of the animal (in our case rabbit) source of cell transplants. While the animal (rabbit) material could be obtained always (!) fresh, i.e. cells are 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 is always a delay between the time of death and the dissection of human fetal cadaver, so that the viability of cells at the time of their implantation into the patient’s body or planting onto the tissue culture medium, is often in doubt.Preparation of fetal cell xeno-transplants begins immediately after death of animal fetus, while preparation of fetal cell allo-transplants must await natural delivery of human fetus, dead for many hours by then.

Let’s review well established scientific data that have explained reasons why fetal cell xeno-transplants can be used instead of fetal cell allo-transplants with a ’state-of-art’ safety: 1/ It has been known since 19th century, and the entire modern cell biology is based on the fact, that all eukaryotic cells in Nature are built and function according to the same laws. In clinical practice of fetal cell transplantation we have been dealing with eukaryotic cells (of mammals) only.

Scientific Basis of BCRO FCT(16)2/ Main cells of the same organ or tissue are the same in Nature, (or nearly the same), regardless of the species of origin, i.e. corresponding cells of the identical organ of different animal species (including man) are biologically similar. We could make a similar statement about any of approximately 200 – 220 types of cells of human or animal body. This scientific ‘principle of organospecificity’, described in German and Soviet/Russian literature decades ago, is still an unknown term in anglophone medical journals. There are no antigenic differences between the corresponding cells of the identical organ of different animal species, including man. This is another proof of ‘organospecificity’.3/ All biological systems in Nature are composed of the same types of molecules. Great majority of proteins from different organisms, including man, is similar over the entire amino acid sequence, i.e. they are homologous of each other and in general carry out similar functions. The homologous proteins evolved over billions of years from a common ancestor, and logically established a ‘principle of homology’. 4/ The basic law of molecular biology, whereby DNA directs the synthesis of RNA, that in turn controls the assembly of proteins, applies to all living beings. Genetic encoding is the same in most known organisms. ’Families’ of similar genes encode proteins with similar functions.

Scientific Basis of BCRO FCT(17)In fetal cell transplantation it makes minimal difference whether one is dealing with xeno-transplantation or allo-transplantation when it comes to science. But there is an enormous difference in medical practice, since with fetal cell xeno-transplantation we can treat already today hundreds of thousands of patients, suffering from those diseases that cannot be cured or treated by any other therapy. Fetal cell xeno-transplants can be prepared for nearly limitless number of patients, even if individually prepared for each named patient, and ultimately at low cost. While there has always been a shortage of human fetal cells and tissues for transplantation, the same is not true for the cells and tissues of animal fetal origin. It has been, and will be, hard to develop fetal cell transplantation as a therapeutic method if there is enough therapeutic material for treatment of a few patients only: this situation has been slowing the progress for many years. D/ Therapeutic use of cell transplants of animal fetal origin in several millions of patients over the last 90+ years has accumulated sufficient data to prove that fetal cell xeno-transplantation is not dangerous to an individual patient or to a mankind. Cell xeno-transplantation has not caused a single fatality in ~5 million patients over 90+ years, or in any way jeopardized the future of mankind. Most researchers believe that xeno-transplantation is exceedingly unlikely to lead to the generation of new pathogens providing that no laboratory ‘hokus-pokus’ is used in defiance of laws of Nature.

Scientific Basis of BCRO FCT(18)The above is particularly true if animal source of cell xeno-transplants is a domestic or laboratory animal from closed colony as required by U.S. FDA regulation ‘PHS Guidelines on Infectious Disease Issues in Xenotransplantation’ of January 19, 2001 (Federal Register, Volume 66, Number 19, pages 8120 – 1). The key premise of the U.S. PHS regulations is to increase the safety of FCT for the benefit of the recipient patient, but also to minimize, or eliminate, any medico-legal exposure for the treating physician as well as the laboratory individually preparing fetal cell transplants for each named patient.

All BCRO fetal cell xeno-transplants are prepared by a primary organ culture, whereby there is an ample time for close observation, to ascertain that each organ culture is free of any disease or abnormality. The most important feature of BCRO’s procedure of preparation of fetal cell xeno-transplants is an attainment of an almost complete immunological tolerance of fetal cell xeno-transplants by the recipient as a result of which there is no need for an immunosuppression whatsoever, since no clinically detectable reactions of patient’s immune system to fetal cell transplantation have been observed or measured.

Scientific Basis of BCRO FCT(19)With BCRO’s method of preparation of fetal cell xeno-transplants the ideal organ culture growth conditions are created for one cell type of a tissue or an organ, necessary for therapeutic effect, unfavorable at the same time for all other cell types of the same tissue or organ, which are useless for treatment and create an ‘antigenic overload’, that triggers immune reactions (which otherwise would not occur). At the same time the antigenicity of fetal cell xeno-transplants is cut to a minimum by the primary organ culture, too. BCRO’s method is equally applicable to the preparation of fetal precursor cell allo- or xeno-transplants.‘Res ipsa loquitur:1/ The natural barrier has been known to prevent transmission of infections between species to a substantial degree: that applies for example to domestic rabbit and wild hare macroscopically unrecognizable from each other.2/ The more distant the species are, the stronger has been this natural barrier. It has been 100% true between rabbit and man. To-date there have been no reports of rabbit-to-man transmission of any virus.3/ No retrovirus has been found in rabbits to-date!4/ Coming from a certified closed colony, the fetal and newborn rabbits have been found remarkably free of any disease.

Scientific Basis of BCRO FCT(20)The BCRO procedure of preparation of fetal cell xenotransplants by a primary organ culture procedure, the final step to assure a nearly complete loss of immunogenicity, permits implantation of fetal cell xenotransplant directly into arteries / veins, into cerebrospinal fluid, into various parts of parenchyma of any organ, including brain (although seldom necessary), into all body cavities, etc., without immunosuppression(!). One of the key reasons for the high therapeutic success rate of SCT by BCRO method is the fact that no immunosuppression has to be used with implantation.

Immunosuppression has been one of the main reasons why the success rate of cell transplantation has been so low in those lands where the use of immunosuppression has been considered mandatory. Besides toxicity to the patients, it is detrimental to fetal cell transplants, because these very young cells are enormously sensitive to any toxin, i.e. all immunosuppressants. Until we learn what life is and can explain various aspects of the function of the living body, we have to be satisfied with the fact that implantation of fetal cell transplants prepared by the ‘state-of-art’ method does not cause clinically apparent immune reactions.

Scientific Basis of BCRO FCT(21)There are many published medical reports showing that changes of laboratory parameters of the immune system function before and after fetal cell transplantation are minimal and statistically not significant, providing fetal cell transplants are prepared ‘state-of-art’. In 1984 the Regulations of USSR Ministry of Health stated: immunosuppression is not necessary for cell transplantation if fetal cell (allo- or xeno-) transplants are prepared by a method such as BCRO type of primary tissue culture.

Clinical practice of BCRO fetal precursor cell transplantation:1/ Cell transplantation is a vastly different approach to medical treatment and cannot be immediately understood by the mind accustomed to deal with (chemical) drug therapy. The therapeutic effect of drugs of chemical origin is not as broad as those of any of the ~ 200 – 220 known types of cells that could be transplanted into a body suffering from a disease(s).Every diseased organ of the body can be treated by fetal cell transplantation, it is just a matter of finding out what type of cells to use for transplantation: that requires knowledge, and clinical sense, since diagnostic possibilities are still inadequate. Diagnostic tools are standard, but the physician/clinician taking care of a patient must evaluate his findings as a pathophysiologist perfectly familiar with function of all organs and tissues on a cytological level(!).

Scientific Basis of BCRO FCT(22)Every disease means that more principal cells of a diseased organ die than are replaced by cell division. When there are too few main cells of any organ of human body left, that organ stops its function , and if such organ cannot be replaced by organ transplant, the human body will stop functioning, too, it all depends if it is an organ without which we cannot live, e.g. heart, brain.

2/ Prescribed fetal precursor cells for a specific patient do not have to be implanted into damaged organ or tissue, i.e. liver fetal cells into liver, but into much more accessible superficial tissues, as for example under the aponeurosis of the rectus abdominis muscle, or deeply subcutaneously in the gluteal area, since transplanted fetal cells find their way into the damaged organ or tissue, as if ‘attracted’ by it. This is known as ‘homing’. Damaged cells of a diseased organ or tissue emit signals to the implanted fetal cells “SOS, we need help”, and within 48 – 72 hours the implanted clusters of cells of a specific (‘prescribed’) organ or tissue of a donor (i.e. fetal cell transplants) disappear from the host implantation site, whereupon an average of 75% of implanted cells incorporate - within 5 to 7 days - in the identical organ & tissue of the host, provided that such organ or tissue is damaged. The more extensive damage of target organ or tissue, the higher proportion of the transplanted cells ‘home’ into that same organ or tissue.

Scientific Basis of BCRO FCT(23)If fetal cell transplant implanted into a patient is the same as that of diseased organ or tissue, then transplanted cells incorporate in the diseased organ or tissue, with therapeutic effect. If fetal cell transplant implanted into a patient is the same as that of normal (‘non-diseased’) organ or tissue, then transplanted cells disperse throughout the organism of a patient, without any therapeutic effect. (Halsted principle, 1909)

3/ Since it is rare that only an individual organ is malfunctioning, i.e. usually the whole organ systems are diseased, it is necessary to treat all ailing organs by corresponding cell transplants. The list of cell transplants necessary for treatment of each patient has to be individually selected in terms of particular fetal cell types, dosage, date and preferred route of implantation. Such list is based on the pathophysiologic diagnosis (-es) of the patient, i.e. the physician must pay attention to the abnormalities of each & all organs and organ systems of the patient and based on that establish a pathophysiologic cytological diagnosis (-es) for the patient.Timing of fetal cell transplantation is extremely important: the sooner after the onset of incurable (or untreatable) disease it is carried out, the better will be the therapeutic results.

Scientific Basis of BCRO FCT(24)Fetal cell transplantation is a surgical procedure indeed, and not a therapy by mass produced drugs. All surgical operations are ‘individualized therapeutic procedures’. Double blind studies have never been used for evaluation of results of surgical procedures. Even fetal cell xeno-transplants are not, and will not, become ‘mass-produced therapeutics’.

INDICATIONS:1/ Diabetes Mellitus, types 1 and mixed 1/2, also type 2 in non-obese patients,

when complications have already developed, such as: a. Diabetic Retinopathy;b. Diabetic Nephropathy;c. Diabetic Polyneuropathy;d. Diabetic Lower Extremity Arterial Disease; as well as

- Brittle Diabetes Mellitus in children; and - Diabetes Mellitus in pregnancy, or diabetes mellitus as a cause of female infertility and of habitual pregnancy loss;2/ Other hormone deficiency disorders, where hormone replacement therapy could not re-establish a normal hormonal balance;3/ Early menopause, and some other serious gynecological diseases, where state-of-art treatment has failed;

Scientific Basis of BCRO FCT(25)4/ Male and female infertility, where usual treatment has failed;5/ Immune deficiency disorders, such as cancer, chronic weakness syndrome, AIDS, etc., as well as autoimmune illnesses; 6/ Aging disease, including dementia, menopause, impotence, depression, etc.;7/ Parkinson’s and other degenerative diseases of CNS, stroke due to blood clot, injuries of central nervous system, acute or old, etc.;8/ Degenerative diseases of cardiovascular system, liver, kidneys, gastrointestinal tract, and other organ systems;9/ Many genetic and chromosomal diseases of children, such as Down syndrome, as well as failure to thrive, mental retardation, frequent illnesses, autism, etc., due to various prenatal, natal and postnatal causes; 10/ Others: burns, reconstructive surgery. Contra-indications:Absolute: terminal stages of disease(s), severe acute exhaustion.

Temporary: acute infection, untreated chronic (focal) infection, uncontrollable severe hypertension, uncontrollable severe allergic status.

A Textbook of Stem Cell Xenotransplantation by E. Michael Molnar, M.D., published in February 2006 in Washington, D.C., U.S.A. 

BCRO RUSSIAN RESEARCH ORGANIGRAM N°1

IIBM

Research Center of Pediatrics RAMS:

(Academician Studenikin)

Divisions of NephrologyHematologyGastroenterologyNeuropsychiatryCardiology

-Genetic diseases, chronic nephritis-Aplastic anemia, M Gaucher-Chronic hepatitis, cirrhosis of liver-Cerebral palsy, Inborn brain damage-Cardiomyopathy

Pediatric Hospital of FirstMoscow Medical School:

(Academician Baranov)

-Collagen diseases

Research Center ofEndocrinology RAMS:

(Academician Dedov)

-Nanismus-Congenital hypothyroidism

First Republican PediatricHospital of MHRF:

(Prof. Dr. Burkov)

-Transplantation of human fetal testis

Rehab. Center of First Moscow Medical School: (Prof. Dr. Grinio)

Muscular dystrophy

Medical Center of the Office of the President of the Russian Federation:

(Prof. Dr. Mironov)

-Down syndrome, pediatric genetic diseases -Immune diseases, incl. AIDS-CT via intra-CSF route for untreatable neurologic diseases

Research Center of Transplantology and Artificial Organs MHRF:

(Academician Shumakov)

-Complications of type 1 diabetes mellitus-Male infertility-Hypo-endocrinopathies

BCRO RUSSIAN RESEARCH ORGANIGRAM N°2

IIBM

Research Center of Emergency Medicine RAMS:

(Prof. Dr. Lebedev)

Divisions of Neurosurgery -Neurotransplantation for Parkinson’s disease, for aphasia after severe brain damage injuries, for post-CVA damage

Burn Injuries (Prof. Dr. Smirnov)

(Moscow Burn Center) -Non-surgical treatment of deep (surgical) thermal burns

Research Center of MedicalRadiology RAMS:

(Academician Tsyb)

-Post therapeutic radiation damage of soft tissues

Research Center ofBiophysics MHRF:

(Academician Iljin)

-treatment of accidental radiation injuries

Research Center of Obstetrics, Gynecology and Perinatology:

(Academician Kulakov)

-Early menopause of various etiologies (inc. castration syndrome)-Endometriosis-Intrauterine brain damage (early treatment)-Infertility, female and male

Research Center of: Human Reproduction MHRF: (Prof. Dr. Vasiliev)

-Male infertility and impotence

Central Institute of Traumatology and Orthopaedics RAMS:

(Prof. Dr. Shaposhnikov)

-Surgery of severe inborn deformities

BCRO RUSSIAN RESEARCH ORGANIGRAM N°3

IIBM

Helmholtz Research Center of Ophthalmology RAMS:

(Prof. Dr. Brovkina)

-Myopathy of eye muscles-perforation of eye after therapeutic irradiation

Fedorov Eye Research Institute (Prof. Dr. Fedorov)

-Retinitis pigmentosa-Diabetic retinopathy

Research Institute of Medical Technology MHRF:

(Prof. Dr. Belych)

-Bio-degradable biopolymers saturated with fetal tissue lyophilisates for surgery (orthopaedic, plastic & reconstructive)

First Stomatological Institute:

-tx of paradonthosis

Abbreviations : IIBM - International Institute of Biological MedicineRAMS - Russian Academy of Medical SciencesMHRF - Ministry of Public Health and Medical

Industry of the Russian Federation

Dr. E. Michael Molnar, M.D., M.S., personally invited “TRANSPLANTATION PROCEEDINGS” to record the entire

proceedings of IIBM conference in Moscow from December 4 till 7, 1995, and publish the same in their usual way and was assured by the President of the Editorial Board that the recording will be done.

Two days before the start of the conference the President of ‘Transplantation Procedings informed Dr. Molnar that the staff of ‘Transplantation Proceedings’ will not come to Moscow without any explanation of the reason.

Under difficult conditions in Moscow at that time IIBM was unable to find a local experts to take care of recording and publishing on such a short notice.

The printed records (all in Russian) of all presentations were collected from authors but never published.

The summaries of work of IIBM are in the author’s books.

IN 2009 an all-day long conference on fetal cell transplantation took place in Moscow with the movie screen in the background of the podium filled up with a photo of the author with the following words:

“Dr. E. Michael Molnar, M.D., M.S., father of cell transplantation in Russia”