MadSci Network: Molecular Biology

Re: What exactly happened that allows...

Area: Molecular Biology
Posted By: Tom Wilson, M.D./PhD, Pathology, Div. of Molecular Oncology, Washington University School of Medicine
Date: Tue Mar 18 08:59:39 1997

As would be obvious to anyone who pays attention to national/world news (vis a vis congressional hearings and presidential commentary), something did happen that has brought the issue of human cloning very much to the forefront. BUT, it is still not "possible" to clone a human being, at least no one has done this or knows exactly how.

What happened is that some scientists from Edinburgh managed to clone some sheep. The exact reference for the publication of these findings in the scientific journal Nature is: I. Wilmut, A. E. Schnieke, J. McWhir, A. J. Kind & K. H. S. Campbell, "Viable offspring derived from fetal and adult mammalian cells", Nature, Volume 385, 810 - 813, February 27, 1997. This complete paper and some scientific and ethical commentary that accompanied it can be accessed from here, a page of the Nature web site.

First, some background on the problem in "simpler" terms than you will find in the paper itself. When a mammalian egg cell is fertilized by a sperm cell, the two each donate "half" of a nucleus. These fuse to form a "complete" nucleus with a full complement of DNA. This DNA is then responsible for directing the development of the animal from that single egg cell. The DNA contains the genetic "blueprint" for how to grow, say, a sheep.

For the most part, all the cells in the body inherit a complete copy of that first nucleus. In other words, all nuclei from adult body cells have the same DNA and therefore contain the same blueprint. The "simple idea" is this - if you could put ANY complete nucleus into the egg cell, it might direct development of an organism. The animal that developed would have an exact copy of the DNA from the cell (and animal) that provided the transplanted complete nucleus. The new animal would therefore be a genetic copy or "clone" of the donor animal. This is distinctly different from an egg cell fertilized by a sperm cell as a consequence of sexual reproduction, in which the resulting complete nucleus is not a simple copy of any single previous nucleus, but a conglomeration of two different ones.

This simple idea of transplanting a complete nucleus from a body cell into an egg cell is NOT new!! It has been tried before, with generally limited success. Before this recent work, the most successful attempt was transplanting a nucleus of a frog cell into a frog egg, which resulted in tadpoles but NOT adult frogs. Why doesn’t the simple idea work that easily? What prevents a nucleus that has all the right DNA from properly directing the development of the organism? These are exactly the kinds of questions the Campbell group was studying.

Basically, a nucleus is a lot more than just a simple sequence of DNA. The DNA is packaged into tight bundles called "chromatin" that can affect the accessibility of the genetic information on the DNA. These chromatin bundles change depending on the kind of cell and the stage of development. Also, DNA in cells is chemically modified by a reaction called methylation, and again this is different among different cell types. These and other factors make any nucleus from an adult cell necessarily different than the nucleus that results from the fusion of the egg and sperm "pronuclei". No one knew exactly how or why, but these factors were generally seen as a severe if not insurmountable obstacle to making the "simple idea" work. In technical terms, nuclei from adult cells were said to no longer be "totipotent" (translating roughly as "all powerful"), EVEN THOUGH they still had the complete set of DNA.

This recent paper from the Campbell group is a huge scientific milestone, since they have proven that adult nuclei can be totipotent if prepared and treated correctly. Without boring you with the technical details, they were able to take nuclei from adult sheep cells and transplant them into sheep egg cells. The resulting egg cells were then grown in surrogate mothers by now-standard techniques of implanting the egg cell into the uterus of the mother-to-be. Unlike in previous studies, the were able to get apparently normal adult sheep.

So what does this mean for cloning humans? The most obvious comment is that since the "simple idea" CAN work for sheep, it MIGHT work for humans too. Mind you, this is by NO means a given. Even for sheep the efficiency of the procedure was quite low. More importantly, sheep nuclei and human nuclei are quite different (thank God), and what works for one will not necessarily work for the other. Could it be that the simple idea will work for humans exactly as it did for sheep? Could it be that it will work for humans, but with different conditions of preparation and handling? Could it be that it will NEVER work for humans, because the restriction of totipotency is more severe for humans? I have no desire at all to delve into the ethics/politics of this situation, but it is certainly the most commonly expressed viewpoint in the last few weeks that these questions should remain as they are now - unanswered.

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