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The ambiguities of the term "totipotent"

Via Wesley J. Smith I learned of this incredibly important recent article by embryologist Maureen Condic. If you are at all interested in the issues of the right to life of early embryos and in the science behind it, go and download a copy of the article immediately. Though I cannot see that Condic actually refers in her article (perhaps it's in the massive footnotes, which I didn't read) to recent research purporting to have created totipotent mouse cells by an extremely simple method of adult cell reprogramming (called the creation of STAP cells), what she has to say is relevant to those claims and is extremely timely.

I had not yet posted about that research for a number of reasons. For one thing, I was waiting for more information. For another, the claimed results had not (as far as I know) been duplicated. (See here for some generalized skepticism about the STAP claims, questioning whether the results will be able to be replicated at all and whether they are even scientifically accurate in their own terms.) For a third, the claims of totipotency in the cells created by the simple method of exposing differentiated cells to stress (such as an acid bath) seemed to rest on the rather shaky evidence that the cells, when subsequently injected into a mouse embryo, migrated all over the embryo including to the placenta. What, precisely, they were doing in the placenta, what sort of placental cells they became, and so forth, remained unanalyzed.

During that time the question was asked in a private Facebook forum, probably apropos of this research, whether, if human cells were de-differentiated to the point of being totipotent, it would be wrong to use them in research. I answered carefully that it would depend on the meaning of "totipotency" and, most crucially, on whether the "cells" were actually human embryos. If human embryos are created in a lab, by whatever method, then it is always wrong to use them in destructive research. In fact, it's wrong to create human embryos in the lab at all. If this process can be carried out in humans and produces embryos, then it is in effect a cloning process, and using it in humans is unethical, however convenient. However, I was extremely dubious that this process was creating mammalian embryos. There were a number of reasons for being dubious. First of all, it seemed implausible that merely subjecting adult cells to stress turns them into embryos! Relatedly, the researchers conjecture that they may be mimicking a process that occurs routinely in the adult body in response to cellular damage as a method of repair. But is human reproduction occurring routinely in, say, men's bodies? Is even mouse reproduction occurring routinely in male mouse bodies? That was enormously implausible. If so, why do we not have virgin conceptions popping up by natural causes from time to time if a virginal female's body responds to cellular stress by producing an "accidentally created embryo"? (Even if the cells produced were not embryos but merely plenipotent, a term I will discuss below, it seems that we would expect a lot more cancers, called teratomas, turning up in adult bodies--for example, in the acidic environment of the stomach. See here. This is a reason to question what is being claimed in this research.) Human reproduction is difficult, even in vitro. That's why human cloning has been so long in coming and has always required an egg. So I was skeptical. Oh, one other thing: Buried in one of the articles is a statement that an unnamed researcher had attempted to insert these allegedly totipotent cells directly into a mouse uterus to see if they would develop as baby mice, with negative results.

Into this atmosphere of uncertainty, Condic's paper comes as a useful and highly informative model of scientific rigor and thoroughness. Though Condic doesn't discuss or question the STAP research directly, she does give us important information about various types of human stem cells and the confusing terminology that surrounds them. If the STAP claims hold up to attempts by other scientists to reproduce the results, Condic's scientific work here will be indispensable to discussion of the ethical implications.

Condic distinguishes between the use of the term "totipotent" to mean something like "capable, if separated from other cells and implanted, of developing all by itself as an embryo" and, on the other hand, to mean "capable of producing all tissue types in an embryo's body." Generally it has been assumed that if "all tissue types" really means all, including placental tissue, then these two meanings of the term will always extend to exactly the same sets of entities. In other words, in much that is written on this subject, it has been assumed that if a cell is "totipotent" in the sense of "able to produce all tissue types an embryo needs to survive, including the placenta," then it follows biologically that, if this cell is separated from other cells with which it is found, it just is an embryo. The analogy is usually made to very early (zygote-stage) identical twinning, in which the two cells of the early embryo can be separated from one another and each develop separately as an embryo. These two cells, then, are totipotent in both of the above senses. The ability to produce placental cells has often been used as a watershed (I have used it this way myself), with the assumption being that, if a de-differentiated, separated human cell has the capacity to be re-differentiated into placental cells as one option, along with all other cell types, it must be totipotent in the sense of just being an embryo which would, if successfully implanted in a woman's uterus and left alone, develop along the normal arc as an embryo, fetus, and newborn child.

Condic challenges this assumption, arguing that, while of course some cells (like those of the two-celled embryo) are indeed totipotent in both senses, it is quite biologically possible for a cell to be "totipotent" in the second sense but not in the first. She suggests that we coin the term "plenipotent" to mark the distinction. She argues that a merely plenipotent cell, by itself, is not an embryo and will never develop as an embryo develops, even under the most favorable circumstances, even though it is capable of re-differentiating into all tissue types, including placental tissue.

Condic states that late morula and early blastocyst cells in humans are examples of plenipotent cells. Because they have not yet been committed to either the trophectoderm or inner cell mass, they retain the ability to develop into the structures made by either of these, which include the various tissue types of the embryo and also the "extraembryonic" structures such as the placenta. However, according to Condic, cells of the late morula do not have the individual ability, separated, to develop into an adult individual as an organism. Hence they are not "totipotent" in the sense that we are all concerned about. That is to say, if one de-differentiated adult cells in the lab to the point that they were "much like" the cells of the late morula or early blastocyst, one wouldn't be creating cloned human embryos.

Therefore, if the new, simple techniques that have just been published for making induced stem cells are really making cells that have the potential to produce placental tissue, that doesn't necessarily mean that they are embryos but rather could more plausibly be taken to mean that they are plenipotent.

However, that may not be sufficient in itself to set prudential worries to rest. How can we be sure? What if we really did accidentally de-differentiate adult cells "too far" and thus accidentally clone human embryos merely by de-differentiation techniques?

Condic helpfully addresses this worry as well, and this may be the most important part of the paper. Condic argues that it is scientifically inaccurate to think of de-differentiating cells as being like rewinding a developmental cassette tape. Her first argument for this point is that the cells of later stages of embryonic development are different in highly specific ways from the cells of the zygote, containing transcription factors that do not occur in the zygote. "Reprogramming" a cell to be plenipotent or pluripotent is a kind of leap from one cell type to another, not a smooth rewinding. If, for example, the new cell type is like the cells if the inner cell mass, these are not somehow "so close to" the cells of the zygote that one might accidentally "go past" the ICM stage and make a zygote. One has just changed a skin-cell into an inner-cell-mass cell, which, like the skin cell, is quite unlike the cells of the 2-celled zygote. The fact that zygote cells and ICM cells (for example) occur close together in time as a normal embryo develops should not be taken to mean that they are so significantly like one another that one might "accidentally" make one while trying to make the other.

Her second argument concerns the crucial role of the cytoplasm produced by the mammalian egg:

At this time, the only known totipotent cytoplasm is produced by an oocyte and contributed to the embryo at fertilization. The fact that oocytes produce the cytoplasmic factors that are required for an embryo to be totipotent is the reason oocytes are used for cloning.


Oocytes are highly structured cells that are uniquely produced by the complex process of oogenesis, which involves a characteristic sequence of gene activation that is distinct from the pattern observed in the maternal pronucleus after fertilization or following zygotic gene activation. Oogenesis also requires information from other cells in the ovary. Moreover, recent work clearly documents multiple oocyte-derived components that are essential for mammalian embryonic development. For example, oocyte-expressed Ooep, PADi6, Nlrp5, Ecat1, and Tle6 are required for the normal function of a critical subcortical cytoplasmic complex, with loss of any of these genes resulting in embryo lethality at the two-cell stage. Maternal expression of Kdm1B, Dmap1, Dppa3, and several others is required for correct DNA methylation and maintenance of genomic imprinting, with maternal gene deletions resulting in death at early embryonic stages. Finally, maternally supplied Brg1 and Brwd1 are required for zygotic gene activation, with loss of these genes resulting in arrest at the two-cell stage. [References silently deleted but available in the article.]

In short, you need a normal mammalian egg to produce an embryo. Condic argues that the crucial role of the cytoplasm produced by the egg explains the extremely short perdurance of true totipotency in the cells of the human embryo: Even a little while later, if cells are split off, there may well just not be enough oocyte-produced cytoplasm for the split off cells to be organisms and to develop as organisms.

She even sketches, while raising some doubts as to whether this process is biologically possible, what it would take actually to create a human embryo by de-differentiation and reprogramming (as opposed to the presently used cloning process involving an evacuated egg), showing that this would not happen "by accident" (e.g., by immersing adult cells in an acid bath).

This does not mean that it would be impossible to make an embryo by reprogramming, but it does mean that it cannot happen ‘‘accidently.’’ And converting an adult cell into an embryo using reprogramming (making an ‘‘induced totipotent cell’’) would be difficult to accomplish, even intentionally.

To convert an adult cell into a zygote, it would first have to be reprogrammed to become a cell that is capable of providing the factors that are normally generated during the process of oogenesis. The simplest way of accomplishing this would be to reprogram the adult cell into an immature oocyte (a distinct state from a pluripotent stem cell that would require different reprogramming factors). The immature oocyte would then have to be provided with all of the cell interactions and ovarian factors required for it to become a mature oocyte. During this process, the normal epigenetic reprogramming and meiotic divisions that occur as part of oogenesis would have to be suppressed in order to preserve the nucleus in a state that is capable of driving human development (this may not be technically or even logically possible.). Once this unnaturally suppressed oocyte had been made, the nucleus would again have to be reprogrammed to a zygotic state, a significant remodeling that normally reflects factors derived from both sperm and egg. If all of this could be achieved, then the ‘‘secondarily reprogrammed’’ totipotent cell would have to be activated to begin the process of development. Then, and only then, would a cloned embryo be produced from an adult cell by reprogramming. And this could hardly happen ‘‘by accident."

Leaving no stone unturned, Condic addresses the issue of blastocyst-stage twinning. Some, including some pro-lifers, have argued that the occurrence of blastocyst-stage twinning means that there are true totipotent cells in the inner cell mass of the blastocyst--cells that would develop as embryos if separated and implanted. Condic rebuts this argument by going into the research on blastocyst-stage twinning. As I understand her argument, she is arguing that twinning at this stage is not accomplished by cells in the embryo that are moving from a zygotic stage forward but rather by cells that are repairing what is a kind of damage (the splitting of the embryo), regenerating the torn-away cells within their own post-zygotic cell lines. Although she does not make this analogy, I suppose that a good analogy might be to the ability of a starfish to regenerate a lost limb. Obviously, we adults cannot regenerate half of our bodies if we are split in half, but apparently a blastocyst embryo can. That, however, doesn't mean that the cells doing the regenerating are zygote-stage (true totipotent) cells.

This article should be required reading for anyone who wants to write on the subject of cell reprogramming and stem-cell research. (I'm lookin' at you, science writers for major news outlets.) In particular, it ought to be required reading for pro-life writers on these subjects. Certainly, if it were possible "accidentally" to reprogram cells to the stage of being embryos, we would have to take an ethically consistent line: In that case, the technique would be unethical to use with humans, as it would be a form of cloning.

However, let's not forget that the anti-life side likes nothing better than to make it sound like pro-lifers want to ban research that sounds innocuous. They are particularly adept at playing the unscientific card that says, "Every cell in your body could be an embryo, so do you shed lots of embryos when you shower?" and pretending that such silly declarations have some sort of relevance to the embryonic stem-cell debate. If skin cells could be turned into embryos merely by subjecting them to an acid bath, I say that this would be a rhetorical godsend to those who want to obscure the distinction between cells and embryos and who want to blur the lines between ethical and unethical stem cell research. We will play into the hands of our opponents in this area if we are too quick to believe that it's just so darned easy to "turn any cell in your body" into an embryo. Right from the outset when this research came to light, my antennae went up: Don't be hasty, as Treebeard would say. Condic's article confirms, in excruciating scientific detail, that skepticism. Let's make the information known, so that our side will be informed. We know that obscurantism is a tool of the left on this issue, so more empirical information can only be helpful. Whether anyone else does or not, we pro-lifers want to know the truth so that we can apply ethical principles to empirical facts. Here are some useful facts to go on with.

Comments (2)

Lydia, thanks for the update. I, unfortunately, don't have time to read the full article, but I'm not trying to write or talk about the topic. Your piece has been an excellent summation for the sake of my own understanding. Keep up the good work.

Thank you, Titus. You're the kind of person I wrote it for!

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