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illustration of an in vitro cloning assay

illustration of an in vitro cloning assay

Science moves fast; last year a scientific article from Shoukhrat Mitalipov’s lab (1) claimed that they had succeeded in cloning a human up to the stage of embryo and produced stem cells from it. I was sceptical back then and commented “Other labs still have to reproduce Mitalipov’s experiments…”. So far this year at least 3 labs (2,3) have reproduced Mitalipov’s work: they have introduced the nuclei of adult cells into oocytes, produced embryos and generated embryonic stem cells from those embryos. This has been –in many ways- a big scientific breakthrough. Now a wider debate should take place to determine whether there is any need to continue producing more embryonic stem cells lines by this method.

Cloned early human embryo (blastocyst) From Tachibana et al. Cell 2013

Cloned early human embryo (blastocyst) From Tachibana et al. Cell 2013

Embryonic stem cells (ESCs) can be propagated almost indefinitely in culture and have the potential to differentiate into any one of the more than 200 cell types in the adult body. These properties make them an ideal tool for research and regenerative medicine. There are currently hundreds of embryonic stem cell lines that were generated from normal embryos. Extensive comparisons between normal ESCs and ESCs produced by cloning may be required to establish their equivalence. The exact number of cells produced by cloning that will be required for doing this is open to question.

In 2006 -before human cloning was achieved- a method was developed for generating embryonic-like stem cells directly from adult cells, without the need of using embryos (4). These cells are called iPSCs. We can produce iPSCs routinely now, through chemical or genetic manipulation of adult cells. Scientists have found that iPSCs are not exactly equivalent to ESCs. iPSCs show different marks that allow for their separation from true ESCs (5). But scientists have also shown (in several animal models) that iPSCs are capable of generating any organ in the body, including the sexual organs . Hence, iPSCs can do pretty much everything ESCs do, regardless of “marks”. Too much emphasis on classifications by marks and fingerprints can be misleading if, at the end of the day, iPSCs act like ESCs.

For the moment, the weakest point of iPSCs is that they are generated mainly by genetic manipulation. This makes their approval for clinical use burdensome; there might be “off-target” effects rendering the cells prone to becoming cancerous. Cloned ESCs do not require genetic manipulation. On the other hand, cloned ESCs may also carry abnormalities, and their genetic material is not 100% identical to the DNA of the individual that was cloned -The mitochondrial DNA belongs to the oocyte’s donor.

There are many ethical problems regarding both human cloning and generation of embryos for medical or experimental purposes. Some countries, like Germany, have pre-emptively banned the creation –by any means- of embryos for research; in the UK there is no such a ban but funding for this type of research needs to be approved by an ethics committee (the Human Fertilisation and Embryology Authority or HFEA). In the US, after the 2009 repeal of regulations imposed during Bush’s administration, there seems not to be a clear framework regarding the creation of embryos (6). The existence of moral issues does not mean that the procedure should be banned outright. Many things that are morally questionable -like wars- are some times necessary. In the case of human cloning and embryo generation -as with war- there needs to be public consensus and general certainty that what we are doing has the right objectives and clear, achievable goals.

For example, if iPSCs made from an adult black mouse are injected into a white mouse embryo, that embryo will give raise to a chimera mouse with black and white patches of cells. This is not the same as naturally crossing a black mouse with a white mouse, where the DNA of the black and white parents will exist in every cell at a 50-50 proportion. The chimeric mouse will be made of a mixture of 100% pure black and 100% pure white cells in every organ; the genetic material will not mix. If chimeric mice are crossed they will produce some pure black and some pure white pups proving that iPSCs can indeed generate every type of cell, including sperm and eggs.
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  • Prof. Dr. Zavos 30/05/2014 at 5:02 pm

    You need to review the literrature a bit more analytically. We created the first human embryos and transfered them in women a long time ago!!! We validated those results some time ago!

    1. Human Reproductive Cloning: The Time is Near; RBM Online, 2003.

    1. Toward scientific discussion of human reproductive cloning; RBM Online, 2003

    1. Evaluation of the embryonic pre-implantation potential of human adult somatic cells via an embryo interspecies bioassay using bovine oocytes.

    Fertility and Sterility 85 (Suppl 1): 1248-1260, 2006.
    1. “Possible Therapy of Male Infertility by Reproductive Cloning: One Cloned Human 4-Cell Embryo” ; Archives of Andrology 52(4): 243-254, 2006

    1. “Human embryo cloning via SCNT with adult fibroblast cells”; BIO Index 27, August 2008, pages 58-63

    You may visit http://www.zavos.org/home.html to see more materials in detail.

  • Coxca 18/05/2014 at 8:29 pm

    I believe that the advancement of science is very important to humanity development, on this focus is necessary to break paradigms about who is bad and who is good for the science. The major result is for the benefit of humanity and the other living organisms. I totally agree with human cloning.

    • Ariel Poliandri 20/05/2014 at 6:16 am

      Hello Coxca,
      I agree, the advancement of science is vital for human progress.
      However, I would argue that a change of paradigm happens when something new or unexpected occurs. Somatic nuclear transfer was carried out for the first time in the ’60 and came to fame in ’97 with Dolly, so it is not something new. Until recently we only lacked the technical ability to do it with human oocytes but we knew that it would be achieved if pressing sufficiently hard. The big question is: what is the point of doing it?

  • Shefali Desai > Gary Baker 14/05/2014 at 5:55 am

    Very true observation. Opening flood gates for people who can misuse the technology.

  • Lillian Cruz-Orengo 13/05/2014 at 9:40 pm

    I totally agree with Ariel. Human cloning is not an appropriate technology. I’m a feminist and I don’t agree with all the manipulation to the woman body that is needed to obtain the prime matter for cloning: oocytes. It is reducing the female body to a manufacture and I can’t see myself and any other woman as “that”. I also have a strong opposition to the “mini-me” fabrication that human cloning entails, regardless of the purpose or how “good” the bio-technique might be. However, I praise people like Ariel that are focusing on developing iPSCs. During my Ph.D. I was working in the field of spinal cord injury and currently focusing on autoimmune-neurodegenerative diseases. I know how devastating neurodegeneration by trauma or diseases could be to quality of life. Having the option of morally acceptable iPSC-derived regenerative therapies brings hope to many, sufferers, clinicians and researchers alike. As Ariel says, it is time to stop racing and start thinking, not only what we want to solve but how and its toll on human dignity.

  • Christine DeCarlo 13/05/2014 at 5:28 am

    Interesting mitochondrial DNA quip. That happened to be part of my letter to the BLM about their equine birth control program being out of balance genetically. It helped neither the wild horses nor mine. In fact my life has been wildly out of balance ever since.

  • Gary Baker, Esq. 13/05/2014 at 5:27 am

    I was reading an article today where a researcher is trying to transfer memories. You know, so people with Alzheimer’s can regain memories, and people could be trained, without going to school.

    Gave me the creeps. I guess it is the potential for abuse (Hmmm … I am your Dear Leader and you remember all the great things I have done for you, and the great debt you owe me).

    What a great combo – regenerate my body and my mind, would I even know I had died? How do I know now, that it has not already happened? Maybe I should start checking my mitochondrial DNA.

  • William Bauser > Ariel Poliandri 13/05/2014 at 5:20 am

    The population is getting older. These individuals will have those medical issues that age brings plus those issues to which chosen life styles will bring to a quality of life. As the population ages, they will be wanting to be interactive and not just sitting and watching the sun rise and fall. Although, there are those who morally wish they would just disappear. So, any regenerative science that can add to a quality of life will add to the “economic” coffers because one will have an active population who is civically engaging and adding more than one form of “moral” value to society. Perhaps, like our space program, much more can be added to the productive capacity of society than it’s cost. And, like the “Manhattan project” mankind’s inhumanity to mankind will need be addressed as a betterment rather than as a better than contest. Philosophy and science need do an improved effort in developing methods than has historically been done, thanks to the McCarthy era which has engendered the postmodernist “fluff.”

  • Paul Lucas 12/05/2014 at 8:33 pm

    The reasoning behind cloning from an adult cell was to circumvent immunorejection. Yes, there are dozens of ESC lines produced, but any tissues from them are, the thinking goes, going to have the immunogenic determinants of the embryo. Placing those ESCs, or tissues derived from them, into a person will set up a rejection response that is currently seen with organ transplants. The recipient would have to be on immunosuppresants for the rest of his/her life and susceptible to infection.

    However, ESCs derived from an individual’s adult cell will have, so it is thought, the immunological determinants of that person. Thus any ESCs or tissues derived from them would be autologous (self) and not set off a rejection response. That is the main clinical driver behind the research.

    • Ariel Poliandri 12/05/2014 at 8:46 pm

      You make a good point Paul. Having an isogenic tissue is certainly a convenient feature for regenerative medicine.
      However -as mentioned in the post- cloned cells are not 100% isogenic.
      iPSCs can be generated by transient or permanent genetic modification; if produced by the former, they are 100% isogenic. My feeling is that somatic nuclear transfer (cloning) arrived 7 years too late for humans. Of course, I may be wrong.

  • William Bauser 12/05/2014 at 8:15 pm

    The debate need be an inquiry into appropriateness of the science and not the consequences at this point in time. Bad science is bad science and good science is good science.
    Regenerative science is a good for those who have an opportunity to have a quality of life that they might not have otherwise. For example, regenerative kidney function with those who have renal disease. The bad is the social engineering to which we have witnessed with the postmodernist rhetoric.

    • Ariel Poliandri 12/05/2014 at 9:02 pm

      I share your frustration with the so called post-modern movement William. But I do not think they will have much to say about this work; they have too much fluff to argue about elsewhere.
      This work is certainly cutting edge and “good” science (in the sense that it is technically challenging but reproducible and that it fits within the frame of current biological theory). The big question is whether it is worth perusing from a material (it is not cheap) and moral point of view. What will the payoff be? My impression is that cloning arrived 7 years too late to be of much use (as we have iPSCs) but, of course, I I may be wrong.

  • Christine DeCarlo 12/05/2014 at 8:06 pm

    wow

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