The Odd Couple of Cloning Research: Mitalipov & Woo Suk Hwang Unite

Remember that old TV show the Odd Couple with very proper Felix Unger and his polar opposite Oscar Madison who has all kinds of baggage?

They’ve cloned it into a remake to be on TV soon here in the US in 2015.

It seems only fitting then that actual human cloning research has a new odd couple of a sorts of its own as well.

Hwang Mitalipov

One part of this pairing is Woo Suk Hwang, who is most well known for past fraudulent and unethical human therapeutic cloning research. Hwang has been making somewhat of a comeback lately (see here).

Perhaps another sign of this resurgence efforts is the news from Science (and source article in Korean) that Hwang is teaming up with US therapeutic cloning pioneer, Shoukhrat Mitalipov, in a joint commercial venture. For more on Mitalipov’s past groundbreaking human therapeutic cloning efforts see here.

The respected Mitalipov and the formerly disgraced Hwang, who is trying to move beyond a dark past, make for an unusual pairing. We might even call them the odd couple of cloning.

The piece from Science on this development by Ahn Mi-Young and Dennis Normile includes the photo above of Mitalipov (left) and Hwang (2nd from right) sealing the deal and provides some background on two:

“Despite his claims being deemed fraudulent by a Seoul National University panel, Hwang was awarded an American patent covering his technique in February 2014. Shoukhrat Mitalipov, of the Oregon Health & Science University in Portland, made a series of breakthroughs in primate stem cell research in recent years. He reported in May 2013 using the Dolly technique, known more formally as somatic cell nuclear transfer, to derive stem cells from cloned human embryos, including from a baby with an inherited disorder. More recently he has published several papers related to gene replacement to prevent inherited mitochondrial diseases. He also founded MitoGenome Therapeutics, reportedly to commercialize his work.”

I don’t know about you, but this venture between Mitalipov’s Mitogenome and Hwang along with BoyaLife, which will reportedly put up more than $90 million into the effort, strikes me as a major development. As I’ve written in the past, collaborations of researchers doing animal reproductive cloning experiments and human therapeutic cloning experiments has complicated implications.

February 15 update: In a more recent interview of Mitalipov in NatureNews, planned research collaboration between Mitalipov and Hwang is denied.

Mitalipov also has been in the news this week for another reason, indicating that he has asked FDA approval to use so-called 3-person IVF “mitochondrial transfer” technology, which shares some technical elements with cloning, to treat infertility. This struck some in the UK including some members of Parliament as surprising as they had been told this technology would only be used to treat mitochondrial diseases.

His company Mitogenome is working in this area. One possibility is that the joint venture in China in a relatively permissive regulatory sphere might allow Mitogenome to immediately start 3-person IVF technology there rather than potentially waiting years in the US for FDA approval. The Science piece only gives some hints as to what may be coming down the pipeline:

“The newspaper says initially work will focus on animal cloning but eventually move on to work with human materials. Mitalipov’s “strength is in primate stem cells. My specialty is in cell nuclear transplantation. So we’ve agreed that if we combine his strength with mine, we can create a breakthrough outcome in curing maternal line genetic disease, on which he is now focusing,” the paper quotes Hwang as saying. Hwang said they will place their laboratory in China to avoid Korea’s strict bioethics regulations.”

It will be important to learn much more specifically what the Mitalipov-Hwang venture will be trying to achieve now and in the future. I have emailed Mitalipov a few questions on this situation to get some additional info and will post his reply if I get one.

13 thoughts on “The Odd Couple of Cloning Research: Mitalipov & Woo Suk Hwang Unite”

  1. Dr. Knoepfler, thank you for providing the forum, and sorry for jumping into a discussion only peripherally related to the original topic. I am grateful to Dr. Loring and mampan7 for furthering my education. Any day that you learn something new is a good day!

  2. Mampan7,

    What changed from the final rejection was the further limitation of the method claims to only cover the KCLRF-BP-00092 cell line. Before that, they were generally claiming that the method could be used to generate SCNT-derived pluripotent cells, and those claims were rejected. Once they limited the claims to only generating the KCLRF-BP-00092 cell line, the claims were allowed.

  3. Dr. Loring,

    Thanks for the clarification! Your explanation makes sense, and I stand corrected. What do you think would be the most reliable way to establish/exclude pathenogenesis, then? Perhaps the SNP/recombination analysis described in the papers cited above by mampan7?

    I am not too surprised by the lack of further publication; I would imagine that the taint from the Science retractions would leave a pretty big stink, and Hwang did have to resign from his position afterwards.

    There was eventually a 2011 paper in the International Journal of Molecular Medicine where they attempted to defend the non-parthenogenic origin of these cells based on the gene imprinting and DNA methylation analyses, but Hwang is not listed as an author. The data from this paper were referred to in the affidavit filed 4/13/2013 by Hwang in support of the patent application. However, the examiner was not convinced by the gene imprinting/DNA methylation data, either (see the office action of 8/7/2013). It looks like what actually tipped the scales over to patentability was limiting the scope of the claims to the KCLRF-BP-00092 cell line only.

    Regardless of the actual origin of the cells, it seems to me that patent claims covering only a single cell line (that has already been generated) would not be particularly useful (especially given the much broader coverage of Mitalipov’s 2011 patent on SCNT), and so I don’t believe that the granting of this patent is as big of a deal as it has been made out to be.

    Additionally, I still believe that the granting of the patent was justified because, regardless of whether the method actually works or whether the cells were actually derived from parthenogenesis, enough detail was provided in the description of the method to conceivably allow someone to generate the KCLRF-BP-00092 cell line, and insufficient evidence was available to conclusively indicate that performing the claimed method would not result in the KCLRF-BP-00092 cell line (or that the cells were obtained by a method other than the claimed method). Data and arguments were presented from both sides, i.e., both supporting and excluding the SCNT origin of the cells, leaving the examiner to conclude that the origin of the cells was “still controversial” in the office action of 8/7/2013. To reject the patent on the basis that there is absolutely no way that the claimed method was used to obtain the KCLRF-BP-00092 cell line, i.e., that the applicant has lied even though they have signed oaths indicating otherwise, would require an extremely high burden of proof for the patent office. This uncertainty is at least partially mitigated by limiting the scope of the allowed claims to cover only the KCLRF-BP-00092 cell line.

  4. SoCalLocal,

    Thank you very much.

    I cannot understand what had been changed from ’08-07-2013 Final Rejection’.

  5. Shinsakan,

    Non-Patent Citations

    18 Kitai et al., “Recombination Signatures Distinguish Embryonic Stem Cells Derived by Parthenogenesis and Somatic Cell Nuclear Transfer,” Cell Stem Cell, vol. 1, No. 3, Sep. 2007, pp. 346-352, XP02471903.

    ( )

    35 Tobin and Kim. Confirmation of Parthenogenetic Identity by Recombination Signature in Human Embryonic Stem Cells. Stem Cells and Development, 2013, vol. 22, pp. 1016-1017.
    * Cited by examiner

    ( )

  6. Shinsakan: Having analyzed parthenogenetic hESCs as well as a boatload of other hESCs and iPSCs, I wouldn’t put much faith in an imprinting pattern. Pluripotent stem cells just can’t hang on to normal imprinting. You can read our 2012 epigenetics paper if you’d like- although you probably should set aside a week or two to get through all the data!

    I have a hard time understanding why Hwang would fail to publish a genuine SCNT line- even if Science weren’t interested, another journal would have considered it if the data were persuasive (and clearly not falsified…).

  7. Mampan7,

    O.k., then how about the comparison between the derived cells and the donor’s somatic cells by PCR and bisulfite sequencing to evaluate the expression and methylation patterns of imprinted maternally and paternally expressed genes, which was also presented in the affidavit of 4/13/2013?

  8. I think karyotype data can not be any criteria to distinguish between the ntES cells and the parthenogenetic ES cells.

  9. Mampan7,

    I am not talking about the figures in the patent publication. The material in the published document is not the only material considered during patent prosecution.

    I am talking about Figure 1 in the affidavit filed 4/3/2013, which shows karyotyping data, not DNA fingerprinting.

    The examiner did indeed consider all available information. Please look at the entire prosecution history and all information on file to understand why the patent was allowed.

  10. Human embryonic stem cell line prepared by nuclear transfer of a human somatic cell into an enucleated human oocyte (US 8647872 B2)

    The patent claims one embryonic stem cell line, KCLRF-BP-00092(claim 1) and a method for preparing an embryonic stem cell line(claim 2).

    They insisted in the patent paper.

    DNA fingerprinting analysis was performed with regard to the genomic DNA and human short tandem repeat (STR) marker using a STR AMP FLSTR PROFILER kit (Applied Biosystems, Foster City, Calif., U.S.A.) with an automated ABI 310 Genetic Analyzer (Applied Biosystems, Foster City, Calif., U.S.A.). The results are shown in FIGS. 6A to 6D.

    As shown in FIGS. 6A to 6D, it was observed that the karyotype of the ntES cells derived from the nucleus-transferred oocyte prepared in accordance with Examples 1 to 5 above was identical to that of the nuclear donor cell. This result demonstrates that the ntES cells of the present invention have been indeed derived from the nucleus-transferred oocyte prepared by transferring a nucleus of a female somatic cell into an enucleated human oocyte, not from a parthenogenetically activated oocyte.

    The Examiner did not recognise.

    FIGS. 6A to 6D is not the ***karyotype*** data of the ES cells and that of the nuclear donor cell, but the ***DNA fingerprinting data***.

    The DNA fingerprinting data of the ES cells derived from the nucleus transferred oocyte prepared in accordance with Examples 1 to 5 above was ***not identical*** to that of the nuclear donor cell. Some markers of the ES cells were same as that of the nuclear donor cell and other markers were different(homogenous) from that of the nuclear donor cell(heterogeneous). This result demonstrates that the ES cells have ***not*** been indeed derived from the nucleus-transferred oocyte prepared by transferring a nucleus of a female somatic cell into an enucleated human oocyte, ***but*** from a parthenogenetically activated oocyte.

  11. Just wanted to comment on an apparent misperception in the news article in Science about Hwang’s patent: Hwang’s patent actually does not generally cover the technique used in the retracted Science papers.

    (1) The patent claims actually allowed, i.e., granted, only cover the preparation of a single SCNT-derived cell line, KCLRF-BP-00092, nothing more.

    (2) The allowance of the claims was not based on the fraudulent data; in fact, the patent application was initially rejected because of the fraudulent data. Other data were subsequently submitted (including chromosomal data indicating that KCLRF-BP-0009 was actually not formed from parthenogenesis) that led to the allowance; this is why the allowed claims only cover a single cell line, i.e., KCLRF-BP-00092, and not the general technique or SCNT-derived cells in general.

    The article makes it sound as though there was something wrong with granting the patent when in fact it was legitimate, considering the scope of what was actually granted.

Comments are closed.