The main challenges for SCNT cloning of human embryonic stem cells

It was intriguing last week to read about another advance in somatic cell nuclear transfer (SCNT)-based therapeutic cloning of human embryonic stem cells (hESC). The first such work was published last year by Mitalipov’s group from OHSU.

This second paper to produce so-called nuclear transfer hESC (NT-hESC) made the important advance to show that it could be done using adult and even old human somatic cells. This is a reproducible technology, which is very important.

However, key challenges and concerns remain for human therapeutic cloning and for potential clinical application of NT-hESC. Below is my list of the top 5 challenges.

• NT-hESC must be indisputably better than human iPS cells and IVF hESCs to be relevant clinically: NT-hESC face very high hurdles. They must be demonstrably better in some key way than induced pluripotent stem (iPS) cells or traditional hESC made from IVF blastocysts or there’s no point in making them. If NT-hESC are only about the same as these other human pluripotent stem cells in terms of most key attributes then given the difficulty of making NT-hESC (even factoring in some anticipated improvements in technology) there would be little reason to make NT-hESC from a clinical perspective. Thus, their production would be limited to intellectual inquiries. While NT-hESC have the potential benefit of being used for autologous therapy (as opposed to IVF hESC being limited to allogeneic use), the other issues uniquely facing NT-hESC including some mentioned below make this trait of NT-hESC probably not enough alone to carry them forward.
• The head start of other human pluripotent stem cells. Human iPS cells were first reported in 2007 and thus have a 7-year head start on NT-hESC.  The first clinical trial using cells derived from human iPS cells began enrolling patients in Japan in August 2013. Traditional hESC made from left over IVF blastocysts have been around much longer and their clinical trials started even earlier (ACT’s trials for MD). So in a sense NT-hESC could are starting far behind from a translational medicine perspective. On the other hand, one might say that the regulatory and scientific hurdles cleared by both hESC-based products and human iPS cell products might pave the way for NT-hESC and speed their translation to the clinic. Perhaps, but perhaps not. It’ll be fascinating to watch how this develops.
• Human egg procurement challenges. The efficiency of making NT-hESC is very low. The legal and regulatory challenges of human oocyte procurement means NT-hESC production must either boost efficiency or find a new source material. For example in the latest paper only 2 lines were made from 77 oocytes. Some have said this is no big deal since the efficiency of making iPS cells is also inefficient. However, there’s a critical difference. When making iPS cells we start with proliferative somatic cells and can essentially use as many as we want (e.g. tens of millions), while in contrast when making NT-hESC each line must be derived using a separate human egg. Therefore, the efficiency of making NT-hESC must either be boosted at least say 5-10-fold or a substitute for human eggs must be found. In regard to the latter possibility, Mitalipov’s group has shown that at least in mice, two celled embryo cells can mediate successful SCNT.
• The dual use dilemma for human cloning. One of the headaches for the advocates of NT-hESC is that potentially each advance in making NT-hESC (therapeutic cloning) could unintentionally also make it easier for some crazy folks to try to actually clone a person (reproductive cloning or “Star Wars” type cloning). Think that reproductive human cloning is impossible? Unfortunately, that challenge is not going to stop people from trying. Further, even failed attempts at human reproductive cloning (and it’s very likely the first attempts at human repro cloning would be horrible failures potentially producing deformed or dead humans) could unfairly, but rather quickly sink therapeutic cloning. I personally do not believe that there is any insurmountable technical obstacle to human reproductive cloning as it has worked for many mammals in the past and animal cloning is more common now than ever.
• Cloning confusion and public opinion. Cloning is a confusing topic for the public. It is not always so easy for people to differentiate between therapeutic and reproductive cloning. Many folks may already think that “cloning” is bad as they conflate all types of cloning together. It is sort of like when people use the umbrella term “stem cells” to refer to all types of stem cells together. Unfortunately some of the people thinking in these overly simplistic ways are powerful political leaders. This remains a practical challenge for NT-hESC. Above is a picture from my book, Stem Cells: An Insider’s Guide explaining the differences between reproductive and therapeutic human cloning.