Mitalipov briefly responds to Egli preprint, stands by human embryo CRISPR pub findings

Shoukhrat Mitalipov
Shoukhrat Mitalipov points to an image of an edited embryo inside an incubator at the Center for Embryonic Cell and Gene Therapy in Portland, Ore. Rob Stein/NPR.org
Shoukhrat Mitalipov
Shoukhrat Mitalipov points to an image of a CRISPR edited human embryo inside an incubator at the Center for Embryonic Cell and Gene Therapy in Portland, Ore.
Rob Stein/NPR.org

There has been a wave of intense discussions both in the public domain such as on Twitter and behind the scenes over the new Egli, et al. preprint that challenges the main conclusions of the Ma, et al. Nature paper from Shoukhrat Mitalipov’s lab.

Ma, et al. reported CRISPR gene editing of human embryos, arguing for a mechanism of HDR-based gene editing relying on interaction of the maternal and paternal genomes in the early embryos. Egli, et al. presented several alternative explanations — mostly involving what would be artifactual outcomes — for why the Mitalipov team saw what they did in the human embryos.

I’m not an embryologist or recombination guru myself, but I’ve been brushing up on them this week, and still don’t quite get how the HDR between the genomes could have happened. But there is a lot of uncertainty about this situation. For all we know, Mitalipov’s team could generally be right, but we all just need more information to understand why as well as what potentially unusual biology and genetics explains it.

Below is a statement from Mitalipov in response to this situation, where he stands by their main conclusions:

“The study co-authors and OHSU welcome scientific discussion and inquiries of our peer-reviewed study published on Aug. 2 in the journal Nature. Our research uncovered a novel mechanism of DNA repair in human embryos, as well as a method to eliminate mosaicism.

“We recognize that these results must be confirmed by additional studies, and that independent verification of important new findings is a cornerstone of science. We encourage other scientists to reproduce our findings by conducting their own experiments on human embryos and publishing their results.

“We stand by our study’s key finding that human embryos are capable of effectively repairing disease-causing mutations by using a normal copy of the gene from a second parent as a template. We based our finding and conclusions on careful experimental design involving hundreds of human embryos.

“The critique leveled by Egli, et al, offers no new results but instead relies on alternative explanations of our results based on pure speculation. We will respond to their critiques point by point in the form of a formal peer-reviewed response in a matter of weeks.”

16 Comments


  1. This is pretty disingenuous, given that it’s almost impossible to get permission to create human embryos for research: “We encourage other scientists to reproduce our findings by conducting their own experiments on human embryos and publishing their results”.


  2. “We based our finding and conclusions on careful experimental design involving hundreds of human embryos.”

    It is terrible enough that so many human beings died in this research, but then to tout the large number of their deaths as a basis for the soundness of the findings and conclusions is even more telling about the lack of moral or ethical regard for human life that many scientists in this field display. This inhumane and amoral quality of the research warrants much more attention than is being given to the quality of the results. But, we do live in an uninformed and misinformed society that for the most part ignore or dismiss these human deaths, because of the shiny baubles that germline editing promises.

    Though let me remind the naysayers, too, that I certainly am not alone in the view that the research involves unethical treatment of human research subjects. Although U.S. federal agencies obtusely continue to fund research with human embryonic stem cells derived from embryos destroyed by third party agents, they still do not fund research that actively destroys them like germline editing. Check the funding acknowledgement of the Ma et al. Nature paper. No ostensible U.S. federal funding is reported, though I would like to know all the sources of the stated institutional support from OHSU.

    James Sherley


    • The authors obtained informed consent from the egg and sperm donors. They explicitly supported the experiments and are certainly free to do so.

      An isolated early embryo in a dish that is never to be put back into a womb is clearly incapable of becoming a human, even with any in vitro culture technology available today. I would even argue that a late term fetus is not conscious, nor is it yet what one considers a human “being”. In any case, absurdly young embryos such as the ones used in this study are clearly not “human beings”. I see no wrong in using hundreds of these embryos. Sounds like good science.

      I am not alone in this view.


      • There are a range of views on the status of very early human embryos of the kind used in this study. While I personally don’t view them as human beings, I do think that they are not just your average cells or group of cells. They are unique and research involving them requires special bioethical considerations. Plus, every embryo produced came from a human egg, a woman had to be an egg donor undergoing sometimes uncomfortable hormone injections, egg harvesting to collect the oocytes, etc. and the risks associated with that procedure are not very clear in the long term.
        Human embryo research more broadly raises other bioethical issues too. For instance, is it always ethically permissible if a project produces embryos (rather than say using frozen blastocysts left over from IVF procedures) for research? A 1,000 such embryos? 10,000?
        More clearcut guidelines/frameworks are needed for addressing such research given how new it is and the associated questions.


  3. The focus in my mind is this statement…”Our research uncovered a novel mechanism of DNA repair in human embryos, as well as a method to eliminate mosaicism.” Eliminate mosaicism?!?! Seriously? My interest is piqued for sure! I can’t wait to hear more about this.


    • ‘Eliminate’ is a very strong word to use about something like this. Also, they did report 1 mosaic embryo so is that “eliminate”? Plus, the degree of mosaicism may vary depending on the gamete donors too. They did seem to make a lot of progress on reducing mosaicism, but overall, since there is some uncertainty about the level of gene editing that actually took place in these embryos, we should be cautious in getting too excited about any of this for a while until the dust settles. For example, if a sizable # of their embryos either didn’t have any gene editing or had Indels that weren’t easily detectable, the mosaicism results may not be accurate as stands.


      • Also, if any repair actually happened, it most certainly isn’t a “novel mechanism” to anyone familiar with DNA repair or population genetics or even fly genetics. Gene conversion is an old, known repair mechanism.


  4. Here are the questions:

    1) Why must a human reach a certain age and stage of development before it is deemed to merit its own life?

    2) Is a society that values and safeguards the life of its youngest and most undeveloped members different than one that does not?

    3) How are human slavery and human embryonism (definite: the political position that early stage humans do not merit legal standing) different?

    Answers?

    – James Sherley


    • I’ve always though that the cells used in such experiments are from cases that have no way for getting into babies anyway.
      * Is it more moral to let such cells to vanish in a closed box somewhere than to use them for experiments that can lead to cures for other ones?
      * Do you suppose that every egg of every woman should produce a baby?
      * Or how do you actually see the right way for such cells?


  5. Dear Martin S.

    Thank you for sharing these thoughts and questions. I share my responses below:

    * Is it more moral to let such cells to vanish in a closed box somewhere than to use them for experiments that can lead to cures for other ones?

    The moral misstep begins the moment the [cells, human embryos] are given to purposes other than insuring their own continued existence and life. Though it may seem a better choice for society to utilize unwanted stored embryonic humans for research instead of discarding them, it is not a better choice for the embryonic humans. This dilemma was created by the early days of assisted reproduction in which aggressive numbers of human embryos were produced and implanted to increase the probability of successful pregnancies. But now, better technology addresses the excess embryos problem going forward. It is the large number of now unwanted embryonic humans in cryo-preservation that is society’s dilemma. Yes, from the perspective of embryonic humans, morally, it would be better that they were allowed to die with our apology for our error in promoting their futile creation than to exploit their creation for other purposes that appeal to us for our benefit. Moreover, this utilitarian research activity also has negative effects on all of us, as another example of our dehumanization of humans that we wish to exploit for our own gain.

    * Do you suppose that every egg of every woman should produce a baby?

    No. But I do maintain that every human, regardless of their stage of development, whether conceived naturally in vivo or in vitro in clinics and laboratories, has an inherent right to NOT be exploited and/or destroyed for the benefit of other more developed humans, no matter how precious they are to us…including ourselves.

    * Or how do you actually see the right way for such cells?

    I’m not sure I understand this question, but perhaps I addressed it in my first response above?

    Regards,

    James


  6. Clearly, opinions vary widely on when during human development a cell or cells become a person.
    As someone who has been working with human cells in the lab since 1990, I personally do not see how 1 or 8 or even 100 cells are “humans”. Common sense to me dictates that they just aren’t the same as the person over there who is breathing, thinking, etc.
    On the other hand, I do believe that human embryos are not ordinary.
    A healthy 100-cell human blastocyst is not the same as just 100 human skin, liver, cancer, etc. cells growing in a dish. In my view as someone who has thought about all this quite a lot, but never made or used human embryos directly, the use of human embryos for research requires greater consideration, bioethics training, and deep contemplation, especially when said embryos are not pre-existing IVF embryos left over in LN2, but are made expressly for research purposes.
    It’s not clear to me how the Mitalipov team views the human embryos they are making and using for research. If as Mitalipov’s quote suggests they have made and used 100s of human embryos then this amplifies the need for clarity. It also invokes issues related to human egg procurement. Taken together, this is where if they were to write a perspectives piece addressing these kinds of questions it would be very helpful for everyone.


  7. I thought the Egli et al. comments were quite compelling. The question will be what assays are needed to definitively answer Egli et al. concerns.

    Even if the modified embryos are not all parthenotes (which remains to be shown…), the genomic assays used by Mitalipov’s groups did not exclude the possibility of large deletions. It is unfortunate that these questions were apparently not raised (or disregarded) during the peer-review at Nature. It’s not a perfect process, but still…

    I suspect that, even with Egli’s BCA and Mitalipov’s response, it is possible that it will not be easy to definitively resolve this dispute.

    In any case, the questions raised have important implications for future studies of human embryos that are almost certainly on their way. I hope future studies will not run into the same traps that Mitalipov’s group did.


  8. Also, this is rather unfortunate and amusing.

    An article published by STAT News on Izpisua-Belmonte, who is a corresponding author on the human embryo paper, is titled “The creator of the pig-human chimera keeps proving other scientists wrong.”

    https://www.statnews.com/2017/08/07/pig-human-chimera-izpisua-belmonte/

    While everyone is human and makes mistakes, the press releases surrounding these scientists raise questions about the role of hype and the search for glory can contaminate the scientific process.

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