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October 04, 2005
Was Dolly the Sheep Really a Clone?
According to a new article in the Journal of the American Medical Association, maybe not. In the clinician's corner section of the latest issue, Irving Weissman writes about the past and future of stem cell research. You may assume that an article in a peer-reviewed journal about such an important and controversial topic such as destructive embryonic stem cell research would be free from ideololgy and would use accurate, medically accepted terms. Unfortunately, this is not the case. Here is a quote from p1363:
A new technology called nuclear transfer allows the production of embryonic stem cell lines from predefined donors, including patients with genetically determined or influenced diseases. This involves removing the chromosomes of an unfertilized oocyte, replacing them with a nucleus from a somatic cell (eg, skin) to form a pseudozygote. (emphasis mine)
The term "pseudozygote" is an interesting one, for nuclear transfer is the identical process used to clone Dolly the sheep. Last I recall, she did not develop from a pseudozygote (which I guess would develop into a pseudosheep), but from the zygote stage of development.
So I quickly did a pubmed search on the term "pseudozygote", and did not find that term used in any medical abstract. I also googled "pseudozygote", and received precisely four hits in English, two of them belonging to this article. Of course, by the time you read this post, it will also be included in the Google search bringing the grand total of five hits.
In other words, it appears that Dr. Weissman simply introduced a new, controversial, unscientific term into the literature without adequate review. This term does not clarify, but actually makes things more confusing. In discussing controversial topics, we need scientists to clarify their findings, not using made-up terms to confuse. What are they trying to hide anyway?
Continuing on...
The inner cell mass cells from these embryoid blastocysts were used to produce nuclear transfer pluripotent stem cell lines (nuclear transfer stem cells). In mice it has been shown that one can produce nuclear transfer stem cell lines from mature cells, eg, lymphocytes, odorant receptor neurons, and skin cells all of these cases the chromosomal makeup of the cell lines is derived from the donor nucleus, while the mitochondrial DNA is largely from the oocyte; because they are mixed chromosomal/ mitochondrial composites, they are not clones.
Weissman claims that the organisms that are the result of nuclear transfer are not clones because they have mitochondrial DNA from the oocyte along with the DNA of the somatic cell used for the nuclear DNA. This is an amazing claim. First, all mammalian organisms derived from somatic cell nuclear transfer (SCNT) have mitochondrial DNA that come from the oocyte. So if Weissman is correct, we have yet to clone any mammals. Dolly the sheep, which also has mitochondrial DNA from the source of the oocyte, is not really cloned. Weissman gives no clue as to what new term he has made to described "cloned" mammals, but I'm sure that will also be forthcoming.
Furthermore, it should be noted that all mammals, including human beings that result from natural fertilization of sperm and ovum, have mitochondrial DNA that comes exclusively from the oocyte. In general, we have DNA in our mitochondria exclusively from our mother. We are also mixed chromosomal/mitochondrial composites.
This is a classic example of using confusing scientific technology to argue a false point. Weissman wants to argue that organisms that result from the cloning process are not really clones. In order to do so, he needs a smokescreen of challenging scientific terms, some of which he makes up, to confuse the point. I believe this is disingenuous. He then makes one more attack on the use of the word cloning:
Production of nuclear transfer stem cell lines for the production of patient-specific transplantable cells is popularly known as therapeutic cloning, but that is neither a scientific nor an accurate term.
No? I'm sure you are waiting for his argument explaining why this cloning should not be used, and his alternative wording. This is what he comes up with:
The term accepted by most responsible groups, including the International Society for Stem Cell Research84 and the National Academies of Science, Medicine, and Engineering,85,86 is nuclear transfer stem cells. Clearly, production of patient-specific nuclear transfer stem cell lines offers an unprecedented opportunity to study these diseases.8
We should not call it cloning, because, well, these two pro-cloning organizations do not want us to call it cloning. This is a fallacious appeal to authority, and is misleading because the term therapeutic cloning is often used in the literature. The attempt to change the clear meaning of this term is simply a manner in which a certain ideology is being advocated. It is one thing to have this type of discourse in a blog post or even an editorial of a paper in which the editor may not have a great understanding of science. To have this in one of the pre-eminent peer-reviewed medical journals is a travesty. Why don't they want to call cloning by what it really is? Isn't science supposed to clarify the situation for us?
Let me try to be clear. Taking the nuclear DNA from a somatic cell and inserting it into an oocyte in order to produce a living organism IS CLONING! It does not matter why this was done - either for "reproduction" or to sacrifice the organism for the sake of their cells. I wish the scientific community, which claims to be only interested in discovering the truth of the natural world, would be courageous enough to admit that.
Posted by OMFSerge | October 4, 2005 | Permalink
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» Outtakes10.05.05 from the evangelical outpost
Was Dolly the Sheep Really a Clone? -- In the latest embarrassment for the peer-review process, the Journal of the American Medical Association has an unbelievably sloppy article in which Irving Weissman invents new terms (pseudozygote?) and tries to c... [Read More]
Tracked on Oct 5, 2005 1:39:12 AM
» It's all in the name from JivinJehoshaphat
I'd like to propose my own "contest" to help those in favor of embryonic stem cell research and human cloning come up with new term/names for human embryos [Read More]
Tracked on Oct 10, 2005 10:52:34 AM
Comments
You seem to imagine this article is an attempt to confuse the debate over embryonic stem cell research by obscuring the language. This seems a rather hyperbolic interpretation of a fairly straightforward review article. In places, you have misunderstood or confused the facts of the issues discussed. In addition, all your examples are taken from just two paragraphs of a 7-page article that is mostly about basic stem cell science and has little to do with cloning.
You are over-reacting even when you accurately report what he says, and that is only a fraction of the time.
Some general issues first:
Was Dolly the Sheep Really a Clone?
According to a new article in the Journal of the American Medical Association, maybe not.
The article says nothing about this. It may be that the logical implications of the article support this conclusion (in fact, they do), but that's far from saying that this conclusion is "according to" the author. He does not say or imply this - and indeed it has little to do with what the article is about.
Also, you keep harping on the fact that JAMA is a peer-reviewed journal to suggest that the journal editors endorse this person's views or are engaged in some sort of conspiracy. While the research reports in the journal are peer-reviewed, the article you cite is a "Special Communication" - a non-reviewed survey of the current status of research, aimed at practicing doctors and written for general educational purposes. Its claims and opinions are not endorsed by the journal.
More specifically:
The term "pseudozygote" is an interesting one, for nuclear transfer is the identical process used to clone Dolly the sheep. Last I recall, she did not develop from a pseudozygote . . . but from the zygote stage of development.
You are certainly correct that "pseudozygote" is a neologism. There's nothing wrong with that. But you don't seem to understand what the author obviously means by that term, and your discussion of Dolly (which is entirely irrelevant to the article you quote) is incorrect.
A "zygote" is a fertilized egg cell. An egg cell receiving a nuclear transfer as part of a "cloning" procedure is not fertilized by a sperm - thus it is not a zygote. It receives all its chromosomes from one source, not from a mixture of the egg's and sperm's chromosomes - also unlike a zygote - and has to be chemically stimulated to begin dividing - again unlike a zygote. If it successfully begins dividing, it may (with very low probability) go on to form an embryo and possibly a live-born offspring, but at no point is it a "zygote". It has zygote-like characteristics - namely, that it has a complete chromosome complement and, with chemical stimulation, may begin dividing to form a blastocyst and embryo - but it is, quite simply, never an egg cell fertilized by a sperm cell and carrying the combined chromosomal complement of both - the definition of "zygote". The sheep Dolly was produced by this procedure, and was thus also not the product of a zygote. (That was, in fact, the whole point of the "Dolly" experiment. If she had been produced from a zygote - a sheep egg fertilized by a sheep sperm - there would have been nothing noteworthy about her.)
Weissman: the chromosomal makeup of the [nuclear transfer] cell lines is derived from the donor nucleus, while the mitochondrial DNA is largely from the oocyte; because they are mixed chromosomal/ mitochondrial composites, they are not clones.
You: Weissman claims that the organisms that are the result of nuclear transfer are not clones because they have mitochondrial DNA from the oocyte along with the DNA of the somatic cell used for the nuclear DNA. This is an amazing claim. First, all mammalian organisms derived from somatic cell nuclear transfer (SCNT) have mitochondrial DNA that come from the oocyte. So if Weissman is correct, we have yet to clone any mammals. Dolly the sheep, which also has mitochondrial DNA from the source of the oocyte, is not really cloned.
Weissman's claim is based on the fact that the mitochondrial DNA of the nuclear-transfer cells comes from the egg donor, and the nuclear (chromosomal) DNA comes from the nucleus donor (the person whose somatic cell was used to created the nuclear-transfer egg) - which are usually not the same organism. This means that the final organism has a mixture of DNA from two different progenitors. A "clone" is defined as an organism entirely genetically identical to its progenitor. (It is in fact a common biological term. There are many clones in nature - including many fungi, some corals, and any plant grown from a cutting of another plant, as is widespread in agriculture.) Organisms produced by somatic-cell nuclear transfer are not, in fact, clones. Although, since it's the chromosomal DNA that's most important and that DNA comes all from one source, it has become conventional to call these organisms "clones", it's not literally true. Weissman is right in this. But he's hardly trying to obscure anything about he process. He makes his claim in the middle of an article explicitly describing the "cloning" procedure, published in one of the most widely-read medical journals in the world.
furthermore, it should be noted that all mammals, including human beings that result from natural fertilization of sperm and ovum, have mitochondrial DNA that comes exclusively from the oocyte. In general, we have DNA in our mitochondria exclusively from our mother. We are also mixed chromosomal/mitochondrial composites.
Y-e-e-e-s . . . and that's why we're not clones. What's your point here?
Weissman is right that SCNT-derived organisms are not technically clones in the literal sense, and you're right that . . . um, non-clones are not clones either. But nobody is claiming that SCNT is just the same as regular reproduction. There are lots of ways to not be a clone.
Weissman: Production of nuclear transfer stem cell lines for the production of patient-specific transplantable cells is popularly known as therapeutic cloning, but that is neither a scientific nor an accurate term. The term accepted by most responsible groups, including the International Society for Stem Cell Research84 and the National Academies of Science, Medicine, and Engineering,85,86 is nuclear transfer stem cells.
You: We should not call it cloning, because, well, these two pro-cloning organizations do not want us to call it cloning. This is a fallacious appeal to authority, and is misleading because the term therapeutic cloning is often used in the literature. The attempt to change the clear meaning of this term is simply a manner in which a certain ideology is being advocated.
No. From the immediately preceding discussion, explained above, he obviously believes we should not call it cloning because it's not cloning - in the literal sense at least. What it is is the production of stem cells through nuclear transfer (which is not cloning because, again, it combines chromosomal and mitochondrial DNA from two different sources, and thus produces an organism that is not genetically identical to either donor) - so he suggests calling them "nuclear transfer stem cells". Tricky, huh? (Note, too, that "therapeutic cloning" does not have a "clear meaning", because, as Weissman points out, the procedure it refers to is not actually "cloning".)
You may be right that changing this terminology will be confusing this late in the game, but he obviously believes that technical accuracy is more important than trying to preserve the "ideology" behind an inaccurate term. You can hardly accuse him of muddying the issue by trying to be more technically correct. (And the terminology does have substantive significance. Some of the debate over "cloning" hinges on the moral implication of creating organisms with identical DNA. Since SCNT does not do that, calling it "cloning" may lead to confused and ill-informed debates.)
Finally, I note that it was the right-wingers who were up in arms over the term "therapeutic cloning" on the grounds that there is no difference between the procedures for "therapeutic" and "reproductive" cloning - and so we should just call them all "cloning". But if that's the case, and, as Weissman notes, that term is technically incorrect, then the right-wingers are arguing for a label that's never right - in view of which, the confusion of changing to a label that is accurate can hardly be worse.
You have gone to some lengths to dissect a tiny part of a perfectly ordinary, general-interest article on research progress. Your analysis is laced with misunderstandings and a rather jumpy insistence that any use of terminology you do not understand or approve must be some sort of nefarious plot. In fact, nothing about this article is a plot, and most of your claims are wrong to begin with.
Posted by: Kevin T. Keith | Oct 4, 2005 5:37:32 PM
You seem to imagine this article is an attempt to confuse the debate over embryonic stem cell research by obscuring the language. This seems a rather hyperbolic interpretation of a fairly straightforward review article. In places, you have misunderstood or confused the facts of the issues discussed. In addition, all your examples are taken from just two paragraphs of a 7-page article that is mostly about basic stem cell science and has little to do with cloning.
You are over-reacting even when you accurately report what he says, and that is only a fraction of the time.
Some general issues first:
Was Dolly the Sheep Really a Clone?
According to a new article in the Journal of the American Medical Association, maybe not.
The article says nothing about this. It may be that the logical implications of the article support this conclusion (in fact, they do), but that's far from saying that this conclusion is "according to" the author. He does not say or imply this - and indeed it has little to do with what the article is about.
Also, you keep harping on the fact that JAMA is a peer-reviewed journal to suggest that the journal editors endorse this person's views or are engaged in some sort of conspiracy. While the research reports in the journal are peer-reviewed, the article you cite is a "Special Communication" - a non-reviewed survey of the current status of research, aimed at practicing doctors and written for general educational purposes. Its claims and opinions are not endorsed by the journal.
More specifically:
The term "pseudozygote" is an interesting one, for nuclear transfer is the identical process used to clone Dolly the sheep. Last I recall, she did not develop from a pseudozygote . . . but from the zygote stage of development.
You are certainly correct that "pseudozygote" is a neologism. There's nothing wrong with that. But you don't seem to understand what the author obviously means by that term, and your discussion of Dolly (which is entirely irrelevant to the article you quote) is incorrect.
A "zygote" is a fertilized egg cell. An egg cell receiving a nuclear transfer as part of a "cloning" procedure is not fertilized by a sperm - thus it is not a zygote. It receives all its chromosomes from one source, not from a mixture of the egg's and sperm's chromosomes - also unlike a zygote - and has to be chemically stimulated to begin dividing - again unlike a zygote. If it successfully begins dividing, it may (with very low probability) go on to form an embryo and possibly a live-born offspring, but at no point is it a "zygote". It has zygote-like characteristics - namely, that it has a complete chromosome complement and, with chemical stimulation, may begin dividing to form a blastocyst and embryo - but it is, quite simply, never an egg cell fertilized by a sperm cell and carrying the combined chromosomal complement of both - the definition of "zygote". The sheep Dolly was produced by this procedure, and was thus also not the product of a zygote. (That was, in fact, the whole point of the "Dolly" experiment. If she had been produced from a zygote - a sheep egg fertilized by a sheep sperm - there would have been nothing noteworthy about her.)
Weissman: the chromosomal makeup of the [nuclear transfer] cell lines is derived from the donor nucleus, while the mitochondrial DNA is largely from the oocyte; because they are mixed chromosomal/ mitochondrial composites, they are not clones.
You: Weissman claims that the organisms that are the result of nuclear transfer are not clones because they have mitochondrial DNA from the oocyte along with the DNA of the somatic cell used for the nuclear DNA. This is an amazing claim. First, all mammalian organisms derived from somatic cell nuclear transfer (SCNT) have mitochondrial DNA that come from the oocyte. So if Weissman is correct, we have yet to clone any mammals. Dolly the sheep, which also has mitochondrial DNA from the source of the oocyte, is not really cloned.
Weissman's claim is based on the fact that the mitochondrial DNA of the nuclear-transfer cells comes from the egg donor, and the nuclear (chromosomal) DNA comes from the nucleus donor (the person whose somatic cell was used to created the nuclear-transfer egg) - which are usually not the same organism. This means that the final organism has a mixture of DNA from two different progenitors. A "clone" is defined as an organism entirely genetically identical to its progenitor. (It is in fact a common biological term. There are many clones in nature - including many fungi, some corals, and any plant grown from a cutting of another plant, as is widespread in agriculture.) Organisms produced by somatic-cell nuclear transfer are not, in fact, clones. Although, since it's the chromosomal DNA that's most important and that DNA comes all from one source, it has become conventional to call these organisms "clones", it's not literally true. Weissman is right in this. But he's hardly trying to obscure anything about he process. He makes his claim in the middle of an article explicitly describing the "cloning" procedure, published in one of the most widely-read medical journals in the world.
furthermore, it should be noted that all mammals, including human beings that result from natural fertilization of sperm and ovum, have mitochondrial DNA that comes exclusively from the oocyte. In general, we have DNA in our mitochondria exclusively from our mother. We are also mixed chromosomal/mitochondrial composites.
Y-e-e-e-s . . . and that's why we're not clones. What's your point here?
Weissman is right that SCNT-derived organisms are not technically clones in the literal sense, and you're right that . . . um, non-clones are not clones either. But nobody is claiming that SCNT is just the same as regular reproduction. There are lots of ways to not be a clone.
Weissman: Production of nuclear transfer stem cell lines for the production of patient-specific transplantable cells is popularly known as therapeutic cloning, but that is neither a scientific nor an accurate term. The term accepted by most responsible groups, including the International Society for Stem Cell Research84 and the National Academies of Science, Medicine, and Engineering,85,86 is nuclear transfer stem cells.
You: We should not call it cloning, because, well, these two pro-cloning organizations do not want us to call it cloning. This is a fallacious appeal to authority, and is misleading because the term therapeutic cloning is often used in the literature. The attempt to change the clear meaning of this term is simply a manner in which a certain ideology is being advocated.
No. From the immediately preceding discussion, explained above, he obviously believes we should not call it cloning because it's not cloning - in the literal sense at least. What it is is the production of stem cells through nuclear transfer (which is not cloning because, again, it combines chromosomal and mitochondrial DNA from two different sources, and thus produces an organism that is not genetically identical to either donor) - so he suggests calling them "nuclear transfer stem cells". Tricky, huh? (Note, too, that "therapeutic cloning" does not have a "clear meaning", because, as Weissman points out, the procedure it refers to is not actually "cloning".)
You may be right that changing this terminology will be confusing this late in the game, but he obviously believes that technical accuracy is more important than trying to preserve the "ideology" behind an inaccurate term. You can hardly accuse him of muddying the issue by trying to be more technically correct. (And the terminology does have substantive significance. Some of the debate over "cloning" hinges on the moral implication of creating organisms with identical DNA. Since SCNT does not do that, calling it "cloning" may lead to confused and ill-informed debates.)
Finally, I note that it was the right-wingers who were up in arms over the term "therapeutic cloning" on the grounds that there is no difference between the procedures for "therapeutic" and "reproductive" cloning - and so we should just call them all "cloning". But if that's the case, and, as Weissman notes, that term is technically incorrect, then the right-wingers are arguing for a label that's never right - in view of which, the confusion of changing to a label that is accurate can hardly be worse.
You have gone to some lengths to dissect a tiny part of a perfectly ordinary, general-interest article on research progress. Your analysis is laced with misunderstandings and a rather jumpy insistence that any use of terminology you do not understand or approve must be some sort of nefarious plot. In fact, nothing about this article is a plot, and most of your claims are wrong to begin with.
Posted by: Kevin T. Keith | Oct 4, 2005 5:44:37 PM
Pseudozygote? You've got to be kidding me. I personally prefer "embryoid blastocysts." The linguistic lengths they're going to now boggles the mind. But I guess if you can't make a good persuasive argument for why cloning should be legal, it's much easier to create new words and try to fool people.
The beauty of this is that I think they're going to these lengths because the public knows or at least is starting to understand what an embryo is.
Posted by: Jivin J | Oct 5, 2005 9:15:00 AM
I'm not sure why you are getting all hot and bothered over the use of the term clone. Whether or not one calls the organisms clones or not is entirely tangential to the question of whether it is moral to use them to derive cell lines.
Weissman's more significant argument is that they can be used for derivation of cell lines, because they "have little or no chance to implant and produce a newborn in any species tested to date." This claim is remarkably similar to one made by William Hurbut and reviewed favorably by Joe Carter over on the Evangelical Outpost (December 9, 2004). I think you'd be better off attacking that line of thinking.
On the question of whether Dolly is a clone, Weissman may be a little pedantic, but his argument has some merit. In plants, for instance, a clone definitely does share both chromosomal and extrachromosomal DNA, so there is some warrant for arguing that animal "clones" with foreign mitochondiral DNA aren't actually "clones." The fact that we all inherit our DNA solely from our mothers is irrelevant, since no one claims tha we are all clones.
Posted by: Nick | Oct 5, 2005 9:59:12 AM
I'm not sure why you are getting all hot and bothered over the use of the term clone. Whether or not one calls the organisms clones or not is entirely tangential to the question of whether it is moral to use them to derive cell lines.
Weissman's more significant argument is that they can be used for derivation of cell lines, because they "have little or no chance to implant and produce a newborn in any species tested to date." This claim is remarkably similar to one made by William Hurbut and reviewed favorably by Joe Carter over on the Evangelical Outpost (December 9, 2004). I think you'd be better off attacking that line of thinking.
On the question of whether Dolly is a clone, Weissman may be a little pedantic, but his argument has some merit. In plants, for instance, a clone definitely does share both chromosomal and extrachromosomal DNA, so there is some warrant for arguing that animal "clones" with foreign mitochondiral DNA aren't actually "clones." The fact that we all inherit our DNA solely from our mothers is irrelevant, since no one claims tha we are all clones
Posted by: Nick | Oct 5, 2005 10:00:41 AM
Kevin,
A few quick points.
1. I guess I could have entitled the post “Pro-cloning researcher states in JAMA that Homo Sapiens that result from somatic cell nuclear transfer technology are not clones, thus resulting in the logical implication that all other cloned mammals, including Dolly the sheep, are also not clones”. Instead, I choose to highlight my upcoming reductio ad absurdum argument. It seems like most understood this.
2. I acknowledge that new technologies sometimes challenge us to deal with established definitions. It is true that most of the time, the term zygote refers to the result of fertilization. However, a pubmed search on nuclear transfer zygotes or cloned zygotes will show a number of instances that the term zygote refers to the cloned organism at the 2 cell stage. Bringing up the fact that there may be a question as to what to call these cloned organisms at the very early stage is understandable – making up a term is not.
3. Far more important, however, is his contention that the mammalian organism that results from cloning is itself not a clone. This is ridiculous. This is from the Roslin Institute, who cloned Dolly:
http://www.roslin.ac.uk/public/cloning.html
Which type? Much confusion happens when people see the word "clone" used. Depending on the age of the dictionary, the definition of biological cloning can be: • A group of genetically identical individuals descended from the same parent by asexual reproduction. Many plants show this by producing suckers, tubers or bulbs to colonise the area around the parent. • A group of genetically identical cells produced by mitotic division from an original cell. This is where the cell creates anew set of chromosomes and splits into two daughter cells. This is how replacement cells are produced in your body when the old ones wear out. • A group of DNA molecules produced from an original length of DNA sequences produced by a bacterium or a virus using molecular biology techniques. This is what is often called molecular cloning or DNA cloning • The production of genetically identical animals by 'embryo splitting'. This can occur naturally at the two cell stage to give identical twins. In cattle, when individual cells from 4- and 8-cell embryos and implanted in different foster mothers, they can develop normally into calves and this technique has been used routinely within cattle breeding schemes for over 10 years. • The creation of one or more genetically identical animals by transferring the nucleus of a body cell into an egg from which the nucleus has been removed. This is also known as Nuclear Transfer (NT) or cell nuclear replacement (CNR) and is how Dolly was produced.
There are literally thousands of examples in the literature of the term “clone” used for organisms derived from SCNT. In fact, there is a journal call “Cloning and Stem Cells”, which I’m sure you read regularly. The results of the cloning procedure, alas, is… a clone. This is not difficult.
4. There has been a clear attempt by those interested in destructive embryonic stem cell research and human cloning to provide such embryos to distance themselves from the term “cloning”, which the public tends to be against. If you really believe that Weissman is merely a neutral scientist attempting to bring clarity by his use of language, and his ideology bears no effect on his use of terminology, you may certainly do so. However, I think that makes it difficult for you to claim to be a member of the reality-based community.
Posted by: Serge | Oct 6, 2005 10:32:00 AM
