Korean Cloning: The Greek Tragedy Continues...

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The NY Times has the dish on perhaps the final tragedy in the fall of Korean stem cell researcher Hwang Woo Suk. Apparently Hwang's lab was the first to derive stem cells from parthenogenesis, or virgin birth, meaning they were derived from an unfertilized egg. "It could have been a seminal finding if they hadn't had their blinders on," one expert told the NY Times. Knight Science Tracker has the full run down on how other news agencies covered this latest twist in the cloning drama.

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The following are what I have learned from the two reports of the SNUIC -- final report and supplement, the PD's book (tranlsation for English speaker's readership will be out in the near future), attending the trial of Hwang, reading thesis of a few young invovled researchers, and numerous news articles and bloggings that are a mix of information and non-information. And, reading Science 2004. And many many articles.

1. Hwang's team must have learned the nature of parthenogenesis soon after they got the referee report in July 2003. I did not ask Cibelli when he was contacted by Hwang's team for advice for the test. Possibly late in 2003. The referee had suggested parthenogenesis and asked for data for proof.

2. Hwang's team did RT-PCR test and FAILED to get paternal gene expression.
They fabricated RT-PCR data for the paper.

3. It is my understanding that Hwang ``commissioned" two people to reproduce parthenogenesis and failed. It seems that it was a secret sort of thing -- possibly even to most of the team members, which must have been related to the fabrication of the papers.

4. The Seoul National University Investigating Committee must have learned of the referee's suggestion of parthenogenesis in testimonies, tested and found the evidence in mitochondria DNA and 48 STR markers of NT-1 cells and oocyte donor's.

5. The committee chair at the college of pharmacology, SNU, being convinced of the first human parthenogenesis, tried to save Hwang Woo Suk and the university tried to make a new program to help the students and researchers to claim the first parthenogenesis and continue their research (presumably with the help of the government. SNU is a national university). Hwang did not budge and chose to ride on the falsehood, and the idea for a new program flopped.

6. The SNUIC with largely different committee members issued the Supplement to clarify the parthenogenesis using five DMR methylation and total 96 STR markers. Again with comparison to the tests on the oocyte donor's

-- The former test confirms the maternal origin of the NT-1 cells.
-- The latter confirms that the NT-1 cells inherited the meiotic crossover pattern.
Together, they prove that the cells were from parthenogenesis of an immature oocyte -- or a secondary oocyte.

7. The writers of Science 2004 must have known that the egg was an immature egg. Look at Table 1, especially the last row, and read a bit of the description in the text of the ``protocol". Be perplexed about the ``neat sampling" of mature eggs, sucess rates, etc. Then you will also agree that they must have known it at the time of the writing.

8. That is about what is in the paper about the poor successful NT-1 cell line so miserably disregarded. The cells were definitely self-renewing. It was very unfortunate, which I believe was related to patent applications. SNU held out for the patent applications paying the maintenance fee until Hwang finally gave up, and the August 2 paper by George Daley and his colleagues was out promptly in Cell: Stem Cell which I got to see recently.

9. The paper by Kim et al shows a characteristic of the meiotic recombination of the DNA, that is the exclusive homozygosity in the central region of the chromosomes, using Affymetrix 500K SNP probes and compares to the parthenogenetic pattern of a mouse. That is the basis of the claim (or reconfirmation) of the parthenogenesis.

-- What the collaboration did not have is the oocyte donor's cells to test and compare.
The consequence is lack of information of LOH (loss of heterozygosity).
The advantage is that they had plenty of SNPs to sweep the chromosomes.
-- It should be important to realize the duplicate alleles in Chr7 and X.
This implies that the cells must be from high passage number(s).
-- That itself is a data. I did not ask when the cells were parceled out, and I did not find the information in the paper either.

10. The NT-1 cells the SNUIC tested were collected from all the parites in possession of the cells in Korea, and most of them must be from (an) early period(s) and a fraction showed a clue that is consistent with the duplicate allele of Chr7. They saw it in one marker.

11. The advantage of the SNU test is that LOH can be seen in the central regions because they had both the NT-1 cells and oocyte donor's cells. In fact, I believe that that was the basis on which they could throw the verdict of parthenogenesis confidently in the Final Report. (it is an important point and had to be picked up.) That was also confirmed by the almost exclusive homozygosity in the central regions. And they entertained the frequency of the meiotic recombination.

``Almost" is the term I used because of the proximity of the line between LOH and ROH
(retention of heterozygosity: it is possible that I made up a new terminology. When meiotic pattern becomes an issue, it will be a useful lingo, in my opinion.) in some chromosomes and I do not know the ``natural" number of base pairs from the centromere at which the crossings tend to occur for each chromosome.

-- I suspect that chromosomes may have their given positions when they line up in the metaphase plate considering that Chr7 (duplicate) and X (lost or gained) seem to be prone to mishaps, for example. In the line-up, Chr7 may not be in the 7th place from whatever the ``coordinate origin" which may be determined from the formation and migration of the microtubles. It will be nice to know. I am looking forward to renumbering them, which will be finally the scientific coordinates. For example, pseudogenes scattered over different chromosomes may be ``explained" even though it could be a fluke that can happen in large number systems. I tend to favor the former.

12. I translated the Supplement into English with the help of a student at MIT who boasts the grammatical knowledge learned at junior high. (I learned Korean grammar when I was in middle school and no complaints.) That will be uploaded to arXiv.org when I find the proper field. Maybe tissue and organs/biology and cross-listed with condensed matter where biophysicists tend to be around -- also the field known for the well-publicized fraud at IBM. The title is ``The First Human Parthenogenesis Discovered in Fraud Investigation (I): Translation of the Supplement to the SNUIC Final Report". It doesn't sound like a seminal paper because the first page is just the cover page. The Supplement starts in the second page.

13. All the others on my odyssey related to the incident will be in `` ..... (II): Luck, Wiles, Loss, and Fab Extravaganza".

14. My take on the potential scenario of the parthenogenote is: A tiny immature oocyte escaped SCNT and electric shock, perhaps stuck on the dish, and a few hours later got
swept into a dish for activation. Everyone is likely to boo, ``what?? 100\% success rate?"

-- For them, I have to make sure to say that there is a claim by one of the committee members that the second author Ryu told him that he did in secret. It is apparent that the immature eggs were to be tossed out. On the other hand, Ryu and his wife had claimed that the immature eggs were used for encleation practice by his wife who was also a (rookie) researcher at Hwang's lab. The latter is printed in SNUIC Final Report and the PD's monograph. When patents and other aspects than science are at the core of teh attention of the authors, no one seems to say anything straightforwardly. Ryu had known that the cells had failed in producing paternal gene expressions before the final version of the paper went out. In other words, he knew that Science 2004 was a fraud.

-- If we assume hypothetically that the 66 immature eggs in Table 1 were bathed in for activation as described in Table 1, but without experiencing cutting, extruding, SCNTing, and fusing by electric shock as implied in the first page of Science2004, then the parthenogenesis success rate was 1/66.

-- I also have to make sure to write that it is an extremely inflammatory issue if Ryu did experiments with immature eggs secretly. Ryu was technically in charge of the lab and did not bother to identify the oocyte donor's ID correctly when he was asked by Hwang. The PD's monograph reads that Ryu did not know who the donor was between two possibilities, and that is most likely to be correct because he was not around when the oocytes were harvested at MizMedi and delivered to Hwang's stem cell lab.
-- What is known as the fact is that there are no records of the immature eggs. If Ryu had done the experiments, secretly meaning conscientiously with focus, it is extremely odd that there are no known records. If that is the case because he has his own records he did not share with anyone, that is a total violation of the collaboration. If he did parthenogenesis experiments purposefully, whether secret or not, and if he completely neglected to document them, that seems to be hard to comprehend.

-- Ryu indicated according to the presiding judge that Kang Sung Keun has the original lab notebook and he kept his own copy that is a photo copy of the original.

Then, the only conclusion one can come up with is that the team wanted to throw out the immature eggs and Ryu and his wife secretly put them in activation dish with others. Now what is very hard to comprehend at that point is that the embryo must have been growing because it was tended. It must have taken up a dish. Furthermore, Ryu was in charge of the lab. Documentation of the traffic of the cells was his job. There are too many rumors. It is possible that the claim of secrecy may not be true even though it was written in a blog site as if it was a testimony of the committee member in the court under oath. (I may upload the clarification if I have a chance to check the court transcript.)

15. The last but perhaps the most important for the issue of``ethics, science, and journal" is the last line in the abstract. I believe that it was a compromise to appease the referee who must have resisted to the publication of the paper claiming the first human (autologous) SCNT embryo stem cell line. Once the journal accepted the RT-PCR data in Fig.4D as the truth, then science dictates that the abstract can NOT read, ``it can be parthenogenetic too." It is a fraud. It is science lost in Science.

-- As an evidence, look at the maternally imprinted SNRPN. It is fully expressed in SCNT-hES-1 while the parthenogenetic Cyno-1 is completely devoid of the gene expression. SNRPN seems to be known from murine embryos to have its methylation completed by the stage of 4-cells, and it is completely consistent with the Cyno-1 data.
The full gene expression is a firm confirmation that the cell has paternal allele. There is no other way. It can not be parthenogenetic. When it can not be parthenogenetic, no science article says that it can be parthenogenetic too. It is not a science paper. Science was abandoned KNOWINGLY as far as I can tell and it was published as the cover page article. Not because of mistakes, or misunderstandings, but purposefully for ``fringe benefits" that was so large as to diminish science into nothing.

I am suspecting that it was Schatten who tipped the scale using his personal leverage he must have had especially in relation to the brief report Simerly et al and exchanges with the team of ACT published in Science in 2003 where they reported the ``missing spindle motor proteins" as the possible wreckers of the primate SCNTing they had been wroking on. I like the demonstration of the chromosome distributions -- normal and scattered. The sense of competitiion must have been enormous, and Schatten must have found Hwang a springboard for himself. Abundant oocytes, ``friendly attitude" of Hwang, and the publication was an opportunity for his leap. ACT had private money, and he had to go for federal funding, which he got based on Science 2004 and 2005. 16M from NIH. He applied for patent, and he asked for the directorship of the stem cell hub being planned in Seoul.

I strongly believe and urge that the correspondence of Schatten with the editor-in-chief should be open for public scrutiny. It was a fraud. If Schatten had not known the problems of the paper Science 2004, it is a huge problem because he was one of the leaders in that field. If he had known, it is worse. It was a fraud.

Schatten's influence and the nonsense in the last line of the abstract was the tipping point that gushed out total nonsense that jolted Korean society, mugged US Congress,

By Sun Hong Rhie (not verified) on 26 Sep 2007 #permalink

What's really amazing is that some Hwang supporters in Korea are already spinning the NYT article into one that supports their agenda. They are twisting the scientists' quotes in the NYT article so that it sounds like they are praising Hwang for a great scientific breakthrough. This is mostly based on a completely biased Korean news article with horrible translation (examples: "If they hadn't had their blinders on" was translated into "if they didn't have people who were blocking their eyes." Also, Dr. Gearhart's quote "Im delighted there was an explanation that didnt involve fraud" was translated into "I'm delighted by the fact that there was no fraud in their discovery.") and the reporter's own prejudice tacked onto the end. The last sentence of the article reads like this: "However, this flexible attitude shown by the U.S. media and scientists forces us to reconsider the current environment of Korean media and the scientific community, which mercilessly ignored a great research accomplishment due to the obsession with a minor fact called 'data manipulation.'"