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Reproductive BioMedicine Online - Volume 34 • Issue 4 April 2017

Reproductive BioMedicine Online

16 April 2017

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Editorial

Clinical embryology

Article

Assisted reproductive technology

Review

Articles

Commentary

Infertility

Article

Periconception, pregnancy and child outcomes

Review

Articles

Reproductive endocrinology and health

Review

Article


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Date Added: 16 April 2017   Date Updated: 16 April 2017
Reviews (2)
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Ke-Hui Cui   03 May 2017
M.D., Ph.D.
FALSIFICATION OF DATA REPORT IN MITOCHONDRIAL REPLACEMENT THERAPY (MRT) WERE POPULAR DUE TO SAFETY PROBLEM Creators of first artificial subhuman baby in human history, John Zhang et al. published his paper in Reproductive BioMedicine Online (RBMO) 34: 361-368, 2017. There are many severe problems in the published paper and other MRT related reports. 1. All of the news were reported that Zhang’s procedures were performed in Mexico. Thus Zhang’s procedures did not violate U.S. regulations. However, this paper showed most of Zhang’s procedures were performed in U.S. and only embryo transfer was performed in Mexico. This paper confirmed that Zhang and his workers broke U.S. regulations in the U.S. territory. Those original news were falsified in order to escape U.S. government punishment. 2. The paper described the stimulation was minimal ovarian stimulation. However, 18 oocytes were collected in the second cycle was belong to hyperstimulation. The author used “minimal ovarian stimulation” in the published paper as his business advertisement, rather than scientifically reported his work. 3. Although editors urged the author to describe the oocyte quality in any depth, the author refused to do so. This was one of the reason that all editors of RBMO were unanimous in deciding that the paper should be published for further critical evaluation and open discussion. All of the oocyte retrieval results and fate of oocytes were outlined in the Table 1 of the paper. The paper described: “Because of the overall poor quality of the oocytes, only nine of the 29 harvested oocytes were found to have a polar body (MII) oocytes”. Was it true? Zhang was reckless. In Table 1, eleven rather than nine of MII oocytes were found. Also, a total of 15 oocytes were described as “degenerate”. What was the reason for so high number of oocytes to be “degenerate”? It was a great issue related to whether the MRT techniques were safe or not. Let us analyze all of the data step by step about Table 1 to confirm the inappropriate report manner. A. In 29 oocytes, there were three oocytes with germinal vesicle. It meant that the cycle stimulation days were not overdue. Under this condition, the oocyte membrane would be tough and was not possible to be broken down during retrieval. B. No MI oocytes were reported. If there was any MI oocyte, it would be reported as the case of germinal vesicle to be reported. C. Although the editors mentioned the possibility of atretic oocytes to be the degenerate ones, the author keep the writing not to be changed. It meant that no atretic oocytes were found. D. Some trick was hidden in the table1. There were two rows of MII oocytes: one row was “MII (spindle visualized)” and another row was “MII without zona”. They hinted more MII oocytes to be possible in other row. Thus the degenerate row was the focus for everyone to guess whether they were the MII oocytes or not. Without spindle transfer experience, no one could guess them correctly. That was the point for the author to “play” the MII data easily. E. There were two MII oocytes without zona. It meant the worker’s skill for hand manipulation in deluting oocytes was poor. He was not a very careful worker. F. After retrieval and oocyte delution, no atretic oocyte and no MI oocyte were found. What were the reason to produce 15 oocytes to be degenerate? If the “degenerate” row was also belong to MII oocytes and some of them were categorized as degenerate by no spindle view, and some of them were degenerated in the courses of spindle aspiration and electrofusion, and also in the later course of embryo death, the editors’ question could be solved. The author avoided to mention any of them for the safety reason. He only put them simply as “degenerate” due to “poor quality of the oocytes”. He showed very nice and very safe results of spindle transfer for FDA to scrutinize, for Human Fertilization and Embryology Authority (HFEA) in U.K. to further support mitochondrial replacement techniques (MRT), and for the world people about his “milestone” work. G. No document could be shown in the world that a mother with mitochondrial mutant load 23-33% would produce poor oocytes with high degenerate rate. This mother had pregnancy for four times. It confirmed that most of her oocytes were good in quality at the MII stage rather than too poor to have polar body. H. In spindle transfer, MII oocytes will not be able to be shown 100% spindle view with polscope. If they can be shown 80%, it will be good enough. The author showed it to be 100% successfully. I. During maternal spindle transfer (MST) or pro-nuclear transfer (PNT) in MRT, chromosomes (spindle or pro-nucleus) of the mother’s eggs (or zygotes) were torn out from mother’s eggs. Microtubules connecting to those chromosomes were also torn, turn to be thin and at last broken down. To use 15 micrometer OD glass needle to aspirate spindle, 80% success rate without cell lyses would be very good. The author and his worker used 20 micrometer OD glass needle to aspirate spindle showed it to be 100% successfully without any cell lyses. J. When the chromosomes were transferred by electrofusion to enucleated donor’s cytoplasm, 90% success rate would be very good. The author showed it to be 100% successfully. K. When embryos showed two pronuclei and grow to blastocyst in IVF, 80% blastocyst rate is very good. The author showed it to be 100% successfully with spindle aspiration and electrofusion reconstructed embryos. The author used very “poor quality” oocytes, and used poor aspiration needle with poor manipulation skill (above E) performed by the reckless worker for the very traumatic procedures. They reported their result data as 100% successfully in the above procedures of H, I, J and K. It meant that the author had used the worst stuff with most harmful techniques, and he would have produced the best results in the world. It was naïve, impossible and inappropriate. Every embryologist still remembers the 15 “degenerate” oocytes, and knows that oocytes with poor quality will never survive well in severe traumatic manipulation, and they will never develop well in later growth and produce live birth. Put 15 oocytes to be “degenerate” but not “MII oocytes” is out of common sense. Those 15 oocytes were not only (MII) mature oocytes with polar body, but also were manipulated by them in spindle transfer. Their results were degenerated. The author wished to set up his “degenerate” model as a new format for pseudoscienticists to follow in their future subhuman reproduction, to elude safety problem. 4. To avoid safety problem, Zhang used another “scientific” technique in his another report paper, which technique may be called “selective data report or part data report”. When he performed PNT in China in 2002 and 2003, total 7 to 10 pregnancies were reported by the news in autumn of 2003, in which five stillbirths happened without any live birth. These data showed very severe safety problem of MRT. U.S. FBI and FDA chased Grifo and Zhang into China and protested to Chinese government. Chinese government – Department of Health immediately banned MRT practice in China in the week of the news report. (That was why Zhang perform frozen embryo transfer in Mexico in 2016). Zhang should report the whole picture of PNT results in China to the public. However, he only reported one pregnancy with twin stillbirth in the 2016 paper after 13 years of the practice in China. The “selective data” report showed much better condition to the public. It was a misleading report. In Zhang’s recent live birth report, the author claimed that only one case of MST was performed. It was forever not possible for the public to know how many cases the author had performed, while “selective data report” existed. 5. .Jacques Cohen also used “selective data” to report his MRT health documents. He performed MRT with 5-10% of cytoplasm transfer which was mild damage to the eggs and embryos, because no chromosome transfer was performed. He only selected 13 from 17 cases to report. His incomplete report still showed the MRT babies (produced by only cytoplasm transfer) are suffering from more immune deficiencies and neuropathy problem than usual incident rate of general population. It showed that the three parents’ proteins and genes may be the factors to harm the offspring’s immune system and mental development by embryonic feedback mechanism which has been confirmed in mouse experiments. The results of the quadruplet which did not be reported are very questionable in safety. If four children were suffering from mental retardation, the safety problem would be much severe. 6. There was no statistical animal research data to confirm the safety question of MRT in the world. The reason was: It was very obvious that MST and PNT were both very traumatic procedures. The statistical results would only show that they were not safe even use the techniques to produce the first generation babies comparing with a control group. If using the sperm and oocytes from the first MRT generation to produce second generation with MRT techniques, the results would have be much horrible while comparing with the control group. How about the third generation and up to ten generation comparing to the control group? That was why in animal research, people could only use birth case report to show a miracle in MST or PNT. The birth report is to show a life can be produced by the procedures but it is not the statistical results to confirm safety issue. This was the same reason why the cloning sheep Dolly was a case report and there was no statistical data to confirm whether the clone techniques were safe or not. Only the statistics is a scientific method for safety research. A case of birth report is not a reason for scientists to change statistics method to be case birth method to confirm safety. To use live birth report with untrue data or selective data to attract public is not scientific but misleading. It is a corruptive business manner reflects to the field of human reproduction. 8. Both electrofusion and virus techniques will harm DNA structures and they are not suitable to be used on human reproduction while germline cells are very vulnerable to anything rather than itself cytoplasm. 9. Professor Sir Doug Turnbull and Sir Dr. Winston in U.K. should change their research manner from case report to more scientific statistics, from clinical practice to more basic research, such as Cell Anatomy. Then they can understand that human cell structure should not be changed for the aim to prevent genetic diseases. The unique natural and normal cell structures in human beings are the basic stone for normal genetic materials to be normally inhered to our generation from one million years ago. 10. HFEA in the U.K. should suspend the issued licence in Newcastle Fertility Centre about performing MRT with PNT or MST techniques. HFEA should avoid using British people as animal to perform MRT. The basic reason is: MRT with PNT and MST techniques will change the normal cell structures in our human beings to be chaotic cell structures, which will produce severe safety problem. MRT will make human reproduction to be changed into subhuman reproduction. Human species will be changed into subhuman species by the change of germline cell structures. Please also read: “ARTIFICIAL NEW SPECIES – SUBHUMAN BEINGS (Abnormal Cell Anatomy of MRT Subhuman Species)” published on ivf.net 09 April 2017 comment for “Method behind first successful mitochondrial replacement therapy revealed” response on 27 April 2017. Ke-Hui Cui M.D., Ph.D.
Ke-Hui Cui   20 April 2017
M.D., Ph.D.
Comment for Editorial: ARTIFICIAL NEW SPECIES – SUBHUMAN BEINGS (Abnormal Cell Anatomy of MRT Subhuman Species) Professor Sir Doug Turnbull wished UK to become the third country to produce artificial subhuman babies. The first baby of this kind of artificial subhuman (in human history) was reported by infamous Dr. John Zhang in 2016 in U.S., with the work performed in Mexico by a technique called spindle transfer. The event was a critical and tremendous signal to our human beings: human species will be artificially changed into subhuman species. Was that a good news or bad news for our human beings? Absolutely, it was a very, very bad news for human beings, patient families and for true scientists. Why? Because the superior hereditary genes, chromosomes, microtubules and mitochondria in the eggs, sperm and embryos (i.e. germline cells) of our nature human beings will be disturbed, torn, mixed and changed. They will be changed into inferior and abnormal genes, chromosomes, microtubules and mitochondria in the abnormal atmosphere, structure, contents and relationship. Human reproduction will be changed to be subhuman reproduction. There are several reported methods for pseudoscientists and money chasers to use subhuman reproduction to damage and replace human reproduction, such as A. Mitochondrial replacement techniques (MRT) (for example: mitochondrial Augment Program by OvaSciences, which suggested artificially extracted mitochondria should be injected into every eggs to obtain human babies). It will produce MRT Subhuman Species; B. Artificial human sperm, oocytes or embryos produced from human stem cells to produce babies. It will produce Stem Cell Subhuman Species; C. Human gene(s) to be modified in human sperm, oocytes and embryos by gene CRISPR techniques to produce babies. It will produce CRISPR Subhuman Species; D. Human cloning to produce Cloning Subhuman Species; … etc. On March 16, 2017, the Human Fertilisation and Embryology Authority (HFEA) in UK changed their work responsibility from human reproduction to subhuman reproduction, and granted UK licence to Newcastle Fertility Centre to perform MRT with pro-nuclear transfer (PNT) or maternal spindle transfer (MST) techniques. From the reported news, meeting conversation and paper reports, PNT and MST techniques have been shown very detrimental effects on eggs, the fertilized zygotes and their future results: from low embryo cleavage rate, low blastocyst rate, high miscarriage rate to high stillbirth rate, when the MRT data were comparing with general IVF results. The inferior results of the subhuman species from MRT are very easy to be understood by the following Cell Anatomy: All chromosomes in the eggs and zygotes are not freely floating in the nucleoplasm and cytoplasm. They are anchored to the nuclear membrane and then further anchored to the cell membrane by microtubules in very good order by natural control system. Such as: No. 1 chromosome connecting to No. 1 microtubule is anchored on part 1 of the egg membrane.… And up to No. 22 chromosome connecting to No. 22 microtubule is anchored on part 22 of the egg membrane, …. Except chromosomes, all of the tiny organelles such as mitochondria (producing energy ATP), Golgi apparatus (producing proteins), … etc. in the nature eggs and the zygotes are all organized well in good order. Near Chromosome 1, there are more Golgi and mitochondria around and connect (or channel) with it due to chromosome 1 is the longest chromosome containing more genes which will produce more proteins and will need more energy. The No. 1 microtubule will be stronger microtubule to hold the heaviest chromosome. Near the Chromosome 22, there are lesser Golgi and mitochondria around and connect (or channel) with it due to chromosome 22 is the very small chromosome containing not too many genes, which will produce much lesser proteins and will need less energy. The No. 22 microtubule will be a weaker microtubule to hold the much lighter chromosome. PNT and MST will: First, tear and break the microtubules in all different length and at different locations; Second, disturb all of the organelles into chaotic order and different location; Third, break down all of the normal configuration and relation of the organelles; and Fourth, the transferred chromosomes will be randomly reconnecting to different microtubules at different location with different length. In all of these severe disturbance during PNT and MST, chromosomal disturbance will produce the most profound influence on the eggs and zygote for future abnormal development or early death of the embryos, fetus, babies and children, … The Pathology and Genetics related the abnormal Cell Anatomy in MRT subhuman species will be outlined as the following: A. NO CONNECTION OF CHROMOSOME. After MRT, if the broken part of the microtubule could not find the opposite part of microtubule or chromosome to reconnect, the related chromosomes will be lost and produce aneuploidy of the cell. The embryos will die, or will survive and produce babies with chromosomal abnormalities. B. ABNORMAL LENGTH OF MICROTUBULES. First, if a short broken microtubule reconnects to another short broken microtubule after MRT, it will produce extra-short microtubule, which will make it easy to be torn apart in cell cleavage. The chromosome reconnecting to this new short microtubule will be lost and produce aneuploidy. Second, if a long broken microtubule reconnects to another long broken microtubule after MRT, it will produce extra-long microtubule, which will wrap around any chromosome(s) like a long rope. The simple and better result of this wrap around chromosome(s) will produce aneuploidy and the embryo dies. The complex results of this wrap around chromosome(s) will produce small chromosomal abnormalities or influence normal gene expression (i.e. to produce new genetic disease) at any later stage of embryo or fetus development, after birth, at childhood, in adult, in aging time, in any future generations. C. CROSSOVER OR TWIST OF MICROTUBULES AND CHROMOSOMES. If microtubules mismatch opposite microtubules with different chromosomes after MRT, it will produce crossover each other or severely twist together by microtubules. a. When microtubule crossover occurs: the eggs or embryos will die in severe condition. In less severe conditions, eggs and future embryos will survive, and chromosomal abnormalities or gene diseases will happen after birth at different ages or in future generations due to the crossover microtubules press, wrap and influence normal action of those related chromosomes and genes. b. When microtubule twist occurs: the eggs or embryos will die because they will not cleave smoothly. D. DISLOCATION OF CHROMOSOMES. After MRT, if No. 1 Chromosome is reconnected to No. 22 microtubule, the No. 1 Chromosome will be pulled by the No. 22 microtubule to the original No. 22 chromosome environment. In that wrong location, there are lesser Golgi and mitochondria around and connect (or channel) with the No. 1 Chromosome. It will make No. 1 Chromosome difficult to obtain enough energy to maintain normal gene function, and difficult to produce enough proteins for cell normally to run on all kinds of function. It will produce gene mutation, metabolic diseases or cancer. Different chromosomal dislocation (from No. 1 chromosome to No. 22 chromosome, X and Y chromosomes) will produce different kinds of unknown genetic diseases and other diseases. Array Comparative Genomic Hybridization (aCGH) technique can find out the above A. no connection of chromosome, but it may not find out the above B. and C. condition. Technique of aCGH is not possible to find out the above D. condition – dislocation of chromosomes. In mice experiments in 1991, embryo cells at 8 cell stage were pressed by glass pipette needles (i.e. let cell organelles to be pressed 3 to 5 seconds) and then the press was released, and all cells immediately restored to their original location and shape. However, it produced two mice stillbirth in 41 offspring. The control group (39 mice pups) were all normal. It confirmed that: even gentle cell organelle dislocation or distortion would severely change cell structure, organ function and life system function. The damage from MRT manipulation (i.e. chromosome transfer) is horrible when comparing with the simple pressing. To greatly disturb all organelles in the eggs or zygotes by MRT will significantly change the natural structure of Cell Anatomy of our human species into chaotic condition. DIFFERENT MRT CHILD WILL HAS DIFFERENT ABNORMAL CELL STRUCTURES IN CELL ANATOMY. THEY ARE NOT THE SAME AS NATURAL AND NORMAL HUMAN BEINGS WHICH CONTAINING ONLY ONE SAME CELL STRUCTURE IN ALL OF THE CHILDREN. Center performing MRT is a factory to produce all new kinds of chromosomal abnormalities or new genetic diseases which we have not known before. All of those new kinds of chromosomal abnormalities or new genetic diseases will be discovered in the life time of those three parent’s children and their future different generations forever. These new diseases will be a very heavy burden to patients’ families and English government forever. Those babies with abnormal cell anatomic structure are a new species in heredity, an inferior species, or MRT subhuman species. There are TWO CHARACTERISTICS IN THE MRT SUBHUMAN SPECIES (SHORT AS MRT SPECIES): ONE IS: THEY CONTAIN THREE PARENTS’ GENES; AND ANOTHER IS: CHAOS OF CELLULAR ORGANELLES IN CELL ANATOMY. Anatomy is the basic stone of human medicine. Cell is the basic stone of our organs and systems in human body. The chaos of cellular organelles produced by MRT will only produce inferior cellular structure (detailed as above paragraph A,B,C and D), inferior cellular function (detailed as above paragraph D), i.e. inferior cells. The inferior cells will only be composed to be inferior organs, and inferior organs will only produce inferior rather than superior systems, thus will only produce inferior and subhuman babies rather than normal human babies. Everyone can reasonably understand it. Is it true in fact? The fact is: It is too early to say the baby produced by Dr. John Zhang is healthy, because the boy’s cells are all containing abnormal cell structure –abnormal Cell Anatomy. His abnormal cell structure will continuously inhere to his offspring forever. It will need two to three generations and up to ten generations to evaluate the safety for any research about heredity or genetic change, which should have a very perfect documentation system for every offspring in all life, and for further generations. In the world, no any center, institute or country has set up this kind of research system, such as: yearly health check,…and up to birth certificate, driver’s licence and social security number specially designed for the MRT species. It also showed that HFEA is not responsible in their MRT job. Without using large number of animal research data statistically comparing the control group to confirm genetic problem, it is not a scientist’s behavior. All of Dr. John Zhang’s reports showed, he had one live birth and 5 stillbirths. Stillbirth is 500% of the live birth. However, in general IVF, stillbirth to live birth will be lesser than 5-10%. That means: MRT with nuclear transfer produced 100 times of stillbirth more than usual IVF. Dr. John Zhang failed to explain why he produced so high stillbirth rate in all of his reports. Abnormal cell anatomy of MRT can be perfectly to be used in explanation of the stillbirth reason for Dr. John Zhang in the following paragraph. Dr. Jacques Cohen performed MRT with 5-10% of cytoplasm transfer which was mild damage to the eggs and embryos, because no chromosome transfer was performed. He only selected 13 from 17 cases to report. He failed in his job responsibility to collect the whole data scientifically and honorably to report to the people. His incomplete report still showed the MRT babies (produced by only cytoplasm transfer) are suffering from more immune deficiencies and neuropathy problem than usual incident rate of general population. It showed that the three parents’ proteins and genes may be the factors to harm the offspring’s immune system and mental development. When small disturbance of cellular organelles by injection 5-10% donor’s cytoplasm, it produced lesser inferior cells than the prognoses of PNT or MST which the chromosomes were transferred. However, the results still showed the inferior function of immune and nervous system in the 13 reported children. The results of another 4 patients which did not be reported are very questionable in safety. When chromosomes were transferred in MRT, inferior organ and system problems were very severe due to the cells lack of energy and lack of normal function, which have been detailed in the above paragraphs about abnormal cell anatomy in MRT. The inferior function of the respiratory, nervous, circulatory, muscular and endocrine system was the reason for the five stillbirth performed by Dr. John Zhang. Birth was a very stressful condition for the fetus and the baby. Endocrine system should be greatly activated to mobilize the respiratory, nervous, circulatory, muscular system to work much harder together for further survival when birth is on the way. The inferior systems which were composed by the inferior cells (disturbed cell structures by MRT) failed to work and the stillbirth happened. If live births happen, those MRT babies’ future will be full of risk, from sudden death (lack of stress reaction), all kinds of severe diseases (which were mentioned above) to short of life span, and adverse future generations. The major cause is: Their cell structures were disturbed by MRT and the cells do not function normally. Mrs. Sally Cheshire (HFEA Chair, a finance and business professional) does not have common sense and scientific background to correctly understand that human beings should not be changed to subhuman being as species. She did not know that MRT will change cell structures in eggs or zygotes, which will make all of the future cells in the MRT babies to be in abnormal cell structures, and will lead to abnormal organ and system functions. Those MRT babies are not the same as normal human species in Science - cell anatomy, in organ functions and in system functions, although their faces and bodies were looked to be the same as normal human. She was not able to collect complete information without bias from other countries such as five stillbirth in China, performed by Dr. John Zhang in 2003. She also failed to correctly and scientifically analyze statistical data to show to the congress the unsafe results of MRT. At last, she granted the licence to Newcastle Fertility Centre to perform MRT with pro-nuclear transfer (PNT) or maternal spindle transfer (MST) techniques. Although she is very kind, she failed in her responsibility by her limited scientific ability. She should resign her employment as chair of HFEA and the licence granted should be suspended. Parliament should waive their decision about MRT, thus to save the luster of Great Britain for the aim of keeping normal and nature human species in England. U.S contains the most advanced scientists and techniques in the world in the field of human reproduction. Why did U.S. ban MRT in U.S. and is happy UK to try it? That is: U.S. threw the “hot potato” to England, and to see how long English can hold it in their hands. Some reporters described the MRT discussion as a political issue, as a religion reason, as an ethical reason or as a safety issue. All of these could not get the key point of the discussion. The key point is: THIS IS THE INTERNATIONAL BIG FIGHT FOR KEEPING NATURAL HUMAN SPECIES NOT TO BE CHANGED ARTIFICIALLY. IT IS A HUMAN AND ANTI-HUMAN FIGHT. DO NOT DO ANYTHING HARMFUL OR BETRAY THE DIGNITY OF HUMAN BEINGS. We (people and true scientists of all countries in the world) have fought for this for twenty years and prepare the fight will last for 3 to 4 centuries. About the abnormal Molecular Biochemistry of the mothers’ eggs, please read: “CHANGING HUMAN BEINGS BY MRT IS MISLEADING AND NOT SCIENTIFIC” published on ivf.net 05 December 2016 comment for “Expert panel approve cautious use of mitochondrial donation in the UK” response on 19 December 2016. Ke-Hui Cui M.D., Ph.D.


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