Fetal precursor cell xeno-transplantation vs. fetal precursor cell allo-transplantation

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Up until now fetal precursor cell xeno-transplantation has been used in over 99.7% of over 5 million patients treated by’ real’ cell transplantation, over a period of nine decades, while the remaining 0.3% of patients have had allo-transplantation. It is hard to statistically evaluate the benefit of the newest forms of stem cell transplantation, i.e. umbilical cord blood stem cell transplantation and human embryonic stem cell transplantation, in actual clinical practice.

Xeno-transplantation is transplantation of cells, tissues or organs between species, i.e. from animal to man or from man to animal, or from one animal species to another, such as from dog to cat, from cat to rabbit, from monkey to goat, from goat to sheep, etc.

Allo-transplantation is transplantation within the same species, from one man to another, from one dog to another, from one monkey to another, etc.

Auto-transplantation is a transplantation from one part of the body to another of the same member of animal kingdom, i.e. to take a piece of skin from the abdomen of the patient and transplant it to the finger tip lost in an accident, or to take an adrenal medulla of a patient and transplant it to the striatum of his brain to treat his Parkinson’s disease, etc.

There is not much difference between cell xeno-transplantation and allo-transplantation in clinical effects. This fact was recognized already by P. Niehans in 30-ies of the last century and by all major personalities of German cell therapy in 50-ies and thereafter. For that reason the west European cell therapists were not concerned about their inability to use human fetal cells in their work because of prevailing ethical, moral, and religious, attitudes in European countries.

The author was brought up by the European school of ’zellentherapie’, that means ’fetal precursor cell xeno-transplantation’. As cell xeno-transplantation was considered in the U.S. a ’quackery’, ’Frankenstein treatment’, anything but a serious scientific effort, the author switched after 1987 to allo-transplantation, i.e. human fetal cell transplantation, against the opinion of top German experts. F. Schmid, the best cell therapist in the world for two decades after the death of the father of cell therapy, P. Niehans, a charmain of both 'committees on zellentherapie' of DeutscheGesundheitsAmt (DGA), the same as U.S. FDA, advised that there is only one difference between Homo sapiens and the rest of mammals: a major part of the frontal lobe of the brain, that animals do not have, but the rest of the body is the same on cytological level, so why to go through the trouble of working with human fetal cells and tissues. And trouble it has been, is, and will be. The author is one of the few physicians and scientists with extensive experience in the clinical use of both human fetal cell transplantation and fetal cell xeno-transplantation, and that applies to the preparation/ manufacture of cell transplants as well as their clinical application.

Human cell transplantation, i.e. allotransplantation, is not, and will not, be better, or superior to cell xeno-transplantation as the therapeutic tool in human medicine, until human beings will be kept in closed colonies, and euthanasia will be permitted in the preparation of human fetal cell transplants, which is unthinkable. The use of frozen superfluous, or redundant, i.e. 'not needed', human embryos from infertility clinics is another form of euthanasia. Cell xeno-transplantation will give the same clinical results as cell allo-transplantation.

Without oxygen the human heart survives 3 ½ to 5 minutes , but after 20 - 30 seconds all oxygen reserves of the body are depleted and a damage to the heart is inevitable. Initial disturbance of cardiac action must be expected after 8 – 10 systoles, i.e. in 10 seconds, and in one minute the cardiac output is reduced to one third.

Human brain post-asphyxia function will cease in 2 – 3 mimutes due to a great energy demand and very small reserves. Electrocorticogram record stops in 12 – 15 minutes, and evoked transsynaptic potentials in 2 – 4 minutes. Cell membranes depolarize in 6 – 8 minutes.

Kidneys survive for 15 – 30 minutes after asphyxia, with a chance of recovery up to 40 – 60 minutes, but never beyond 60 minutes.

Impairment of pulmonary function after asphyxia alone takes place in minutes to a few hours, but if there is an additional lung pathology present, then only a few seconds to minutes. VI.BIBLIOGRAPHY [286]

The data from the last 3 paragraphs explain why the quality of fetal precursor cell allo-transplants can seldom match that of cell xeno-transplants.

Experienced scientists and clinical specialists in the field of fetal precursor cell transplantation doubt that embryonic stem cell transplantation, that currently by erroneous definition means ’human’ embryonic stem cell transplantation, could be of any value in the actual 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 cells cannot survive in a laboratory dish. Is it just a feeding or is it in reality a co-culture of human embryonic stem cells and mouse feeder cells. And what is the outcome of such co-culturing is a question that needs an answer.

Our team studied the poor results of human fetal cell transplantation (or neurotransplantation) in Parkinson’s disease. With permission of the Ethics Committee of the Russian Ministry of Health the transplantation of brain cells of various genetic mutants of Drosophila, the first member of animal kingdom where a complete mapping of genom was carried out, to moribund patients after severe gunshot injuries of the brain, was carried out, followed by a detailed autopsy. There was no clinical effect from such neurotransplantation but also no histologic evidence of any harm. The next step was a neurotransplantation of a mixture of brain cells of various genetic mutants of Drosophila with human fetal brain cells from basal ganglia and other parts of the brain. The positive clinical results led to the treatment of posttraumatic aphasia patients, and eventually patients with Parkinson’s disease using the combination of human fetal brain cells with brain cells of a genetic mutant of Drosophila. The excellent results of such neurotransplantation in Parkinson’s disease have never been surpassed. VI.BIBLIOGRAPHY [220] One of the patients described in this report died of myocardial infarction 8 months later and a permission to carry out a full autopsy of his brain was obtained. The published microphotographs show excellent synaptic connections of the host brain neurons with the implanted neurons of human fetal origin and neurons from the genetic mutant of Drosophila. There was no histologic evidence of any scar tissue between the host brain and transplant. Transplanted tissue of Drosophila consisted of large multipolar neurons 2 – 5 times larger than thalamic neurons of the host. Human neurons and Drosophila brain cells formed connections via collateral axons. Multiple bundles of 50 to 200 neuronal fibers connected host brain and transplanted tissue. Capillaries and arterioles penetrated between transplanted and host tissue running parallel with neuronal fibers.

The background of this research was the fact that human fetal brain cells are too slow in their differentiation, as the full growth and development of dendrites, axons and synapses is not attained until 4th year of life, so that they do not make connections with neurons of the host fast enough, while in Drosophila, with a life span of only 3 months, the nerve fibers and synapses develop quickly. The enormous clinical success in transplantation of the mixture of brain cells of the genetic mutant of Drosophila and that of human fetus, proven also by the histologic findings, was explained by a hypothesis that the quickly growing and differentiating brain cells of Drosophila enabled in some way the transplanted human fetal brain cells to establish synapses with the host neurons much faster. Obviously the excellent clinical effect was the result of the synaptic connection between neurons of the host and transplanted human fetal neurons, but the clinical success was possible only due to mediating effect of the brain cells of genetic mutants of Drosophila. VI.BIBLIOGRAPHY [220, 221]

This example is presented to trigger a debate about the feeder cells and their use in a Petri dish in laboratory conditions or the use of feeder cells in situ, when a ’co-culture’ takes place in the recipient organ of the host.

In the introduction we alluded to a classical microphotograph of the human product of conception at the stage of blastula with 107 cells, of which only 8 cells become the embryonic stem cells while the remaining 99 cells differentiate into trophoblastic cells of placenta. At that point of development all these cells are the same, and those that will become trophoblastic cells have the same potential for growth and development as embryonic stem cells. If scientists believe in superiority of human embryonic stem cells over fetal precursor cells they have to turn the attention to the trophoblastic cells where they encounter much less moral, ethical and religious outrage, and follow the path so well lit for them by around 20 million patients that received trophoblastic cells implantation in the past.

In the meantime our research focus is on animal trophoblastic cells, specifically of rabbits. Most of knowledge in the field of human embryonic stem cell transplantation has been obtained from mouse embryonic cells. Besides karyotyping there are no dramatic differences between human and mouse embryonic cells, and 99% of human genom can be found in the nucleus of mouse cells. The case is the same with rabbits.

In the field of fetal precursor cell transplantation it makes very little 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 precursor cell xeno-transplantation we can treat hundreds of thousands of patients already today while with stem cell allo-transplantation only a few hundred, or perhaps thousand. Fetal precursor cell xeno-transplants can be prepared in nearly limitless quantities, and ultimately at low cost.

It has been, and will be, hard to develop fetal precursor cell transplantation as a therapeutic method if there is enough therapeutic material for treatment of just a few patients only: this situation has been slowing the progress for many years.

Well established scientific facts have explained the reasons why fetal precursor cell xeno-transplants can be used instead of 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 precursor cell transplantation we have been dealing with eukaryotic cells (of mammals) only.
  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 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 literature. The explanation can be found in various parts of this text. 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 thereby 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. All that implies that life on Earth evolved only once.

The described scientific data explain why it has been possible to implant live fetal precursor cell transplants prepared from sheep, cattle, pigs, horses, rabbits, and probably other mammals, in 5 million patients over the past 90+ years, without any serious consequences for individual patients or mankind.

The first in the world clinical xeno-transplantation of cultured pancreatic islet cells originating from pig fetuses was performed at Soviet/Russian Institute of Transplantology and Artificial Organs of the Ministry of Health ( RITAOMH) in 1981. Besides pig fetuses also adult pigs, cow fetuses, and lately fetal and newborn rabbits, have been used by RITAOMH.