Tuesday, November 22, 2005

Liberal scientific ranting on cloning, stem cells, and life

Inspired by Pinko Punko's latest rant about the impossibilities of having a reasonable argument with those opposed to logic, science, and rationality, I hereby offer my own personal rant based on recent discussions I've had with scientists and lay people about recent advances in stem cell biology.

To begin the rant, let me just say that I'm sick of being called a liberal elitist. I happen to be liberal and I happen to have scientific knowledge in a field that most people are just pure poseurs or parrots. Well guess what: Espousing demonstrable scientific fact as knowledge is not elitism. Performing experiments and analyzing data from the literature is not elitism either. It is a necessary part of the scientific process. If by having a Ph. D. in the biological sciences necessarily defines me as being elitist, and if you are unwilling to engage in conversation with someone you view as being an elitist, just stop now. Don't bother. Most scientists have Ph. D.s and many of us were trained in academia. Good liberals, almost by definition, are not elitist and I don't think scientists should have to put up with these stupid titles, just because other people don't understand our work.

I don't feel like defining all the terms and processes involved here. The basics are as follows: embryonic stem cells are capable of generating all the cells of the embryo proper and we make embryonic stem cells by isolation of the inner cell mass of the blastocyst. We can obtain blastocysts any number of ways, but the ones at stake here are those generated through in vitro fertilization or those created via nuclear transfer, in a cloning experiment. The blastocysts used to make embryonic stem cells are all 'extras'. None of them will ever be implanted into a woman and in the case of cloned blastocysts, none of them have the potential to create a viable neonate. These are embryos that are targetted for destruction, either through thawing (since most are currently stored (at a high cost) in liquid nitrogen) or through epigenetic catastrophe (for cloned blastocysts). The fact of the matter is that we cannot make a viable human embryo through cloning, even if we wanted to. We can make mice, sheep, and dogs through the existing cloning technologies, but not primates. Scientists in South Korea have tried this many hundreds of times with primates. It doesn't work. Their potency for life is zero. However, cloned primates do make wonderful embryonic stem cells, with full potency to generate any somatic tissues.

Next, I think I'm going to define this argument as a 'we' versus 'they'. Who are 'we'? We are scientists and lay people that actually want the science and possible medicinal applications of stem cell technologies to go forward. We believe that it is ethical and moral to either take existing discarded blastocysts, or even create new ones through cloning, and generate ES cells from these blastocysts. Who are 'they'? Collectively, they are opposed to 'us' because they either view this process as a form of murder or the concept of cloning freaks them out because of the remote (and currently unfounded) possibility of using cloning to make cloned human beings.

I think it is appropriate to be confrontational on the issue of 'us' versus 'them'. This is because neither of us offers a middle ground, and there is no point to negotiation of the terms. Science and religion are necessarily incompatible, and arguments founded on one or the other are irreconcilable. I make no apologies for falling on the side of science. I do not believe that I need to be sensitive to theists that demand policy be enacted solely based on religion. Smart theists have a personal belief of god that does not encroach on their ability to think rationally about science. At the same time, as an atheist, I believe in personal freedom of religion, and make no efforts to ban theists from having their beliefs. Scientists seem stuck in the middle of this need to apologize for doing our work without god in the equation. I think we need to move past the apologies and I offer none.

To tackle the first group of 'them', we have the so-called 'pro-lifers' (a noxious and laughable term, given that many of them endorse the death penalty - I prefer to call them anti-abortionists or just plain simple luddites). These people begin by making the assumption that human life begins at the moment of conception, an idea supported by subsets of Christian sects. Thus, to 'them', a blastocyst in vitro is a pure and holy form of life, no different in their eyes, than a similar blastocyst, already implanted in the uterine wall of a healthy woman. Are these equivalent forms of human life? I don't see how it is possible. In culture and left alone, the blastocyst in vitro will continue to divide a number of times and generate various embryonic structures, before eventually atrophying and dying. There is no way to generate a viable neonate outside of a mother. The implanted blastocyst, however, when left to its own devices in a healthy woman, will continue to develop until it eventually forms a differentiated central nervous system capable of sustaining the life of that fetus, and it should be born healthy and viable. Why is it a problem destroying the blastocyst in vitro then? They would argue that the blastocyst, if transplanted into a healthy woman, is capable of generating life. So, if manipulated, the blastocyst in vitro CAN generate a healthy neonate, but only if intervened. The cloned blastocyst is a different case, however. It retains no potency for life in vitro, or when intervened.

As a side note, it is useful, especially in the context of defining abortion laws, to define the point at which an embryo gains certain rights of autonomy or when we transition from cellular life to organismic life. One could argue that this can be medically defined by the point at which the embryo, when removed from the mother, and with the best state-of-the-art medical care, can survive to adulthood. By this definition, the onset of autonomy varies with medicine and is not static. One hundred years ago, it was probably 7 or 8 months. Now, it may be half that time. Clearly, an embryo removed from the mother at the blastocyst stage will die, irrespective of the state of medicine. I prefer those that attempt to define the beginning of 'life'
using the same criteria that we define the end of life - that is with the EEG, a recording of electrical signals from the brain. A human without an EEG is destined for death, first of the organism, and then eventually, all the cells within. At the same time, an embryo without an EEG is incapable of self-sustaining life. The EEG is still arbitrary. Personally, I think the CNS and especially the hindbrain, needs to be further developed before autonomous life is possible. But why split hairs? What is incontrovertible to me, and the key point of this discussion, is that a cultured blastocyst should not have intrinsic rights. It is not a human being and destroying it is not murder. There is nothing magical or holy about a blastocyst. We can create them and destroy them at will, and we need the legal rights to do so without hindrance and without reservation.

I routinely hear the argument that this position is too black-and-white, that the blastocyst is more complex than I make it out be. This drives me insane. How is a blastocyst complicated? We can isolate any cell from it, and define its precise potency. We can grow them in vitro and we can generate them even by tissue recombination. We understand many of the genes required for these functions and can and have tested the requirements of these genes. If there's a soul inside a blastocyst, I haven't seen it isolated, not have I seen that it is necessary or sufficient for the development of that blastocyst. Like the description goes, a blastocyst is a big ball of cells and nothing more.

Unfortunately for us, they currently are in control of the politics and legislation surrounding the use of our science. This means that until the American public extracts their collective heads from their bowels, we are stuck in a position of conciliation. OK, how do we work with them on advancing stem cell technologies. Their main objection is that life (as THEY define it) is destroyed in order to create stem cells. What if WE found a way to make human ES cells without destroying life? Would that be OK with THEM?????? Two recent papers have suggested ways to do this that will force them to re-evaluate their objections to stem cell cloning and I think both are worth discussing here.

The first approach is to use altered nuclear transfer to generate ES cells. The idea is that IF we could use nuclear transfer to generate a blastocyst without potential to generate extraembryonic tissues (and hence one that could never implant in a female), THEN that blastocyst has no potency for life and THEREFORE destroying it would not be akin to murder. Let's put aside for now the very important fact that cloned blastocysts already have no potential for life. THEY refuse to believe our science on this. Well, no problem. The Jaenisch lab (who to their credit have strongly come out against the need for altered nuclear transfer to begin with) has accomplished this in mice. Their strategy is simple, elegant, and immediately applicable to humans. Basically, clone a blastocyst from a cell that is infected with a conditionally active small interfering RNA directed against a transcription factor, Cdx2, which is required for generations of the trophectoderm. Such cloned blastocysts are fully capable of generating ES cells from their inner cell mass, but when transplanted into pseudo-pregnant females, do not implant and shortly die. The beauty of the conditional approach is that even though Cdx2-deficient ES cells are pluripotent and behave like normal ES cells, they still don't form a proper intestine. No problem: in the ES cells, just remove the small interfering RNA via site-specific recombination, and you create an ES cell indistinguishable from a healthy non-manipulated ES cell. Problem solved!

Are we ever going to use altered nuclear transfer? Probably not. For one, the public is still repulsed by nuclear transfer. It's a case of ignorance, superstition, and hypothetical cataclysm. Secondly, the public is not going to support genetic manipulations of such cloned cells, either using a retrovirus (an HIV based lentivirus for the study in question) or using homologous recombination. We'd have to suffer through the whole superbaby sh*t. Even though it offers the possibility of accurate gene therapy and a cure for hundreds of diseases, I don't see this happening, and I don't think it's time for this war yet. Interestingly, this will be why people object to altered nuclear transfer. Additionally, because the Cdx2 gene is only conditionally inactivated, hard-core member of 'them' will oppose the technology because the potential for life would be there if: i) you re-activate Cdx2 expression, ii) you implant the cloned blastocyst into a female, and iii) you somehow learn enough about epigenetic catastrophe to rescue the viability of cloned embryos. Thus, they will still equate it to murder. Well, I would argue that by those definitions, sneezing is also murder, since it leads to the death of mucosal epithelial cells that could generate a viable new human if we only cloned it, transferred it into a female, and solved the mysteries of epigenetic catastrophe. They lose on that argument, because the potency of any cell can be fully realized by cloning, therefore either all cellular death is murder, or none of it is.

Here's where it gets even better for us. Their current unifying opposition is based on the destruction of the blastocyst to create ES cells. Well, what if we could generate those same ES cell lines without actually destroying the blastocyst? How could that possibly be considered murder? It's brilliant! The Lanza group has developed a technique to isolate single blastomeres from the inner cell mass of a blastocyst and create ES cell lines, without compromising the ability of that blastocyst to generate a viable neonate after implantation. It uses a biopsy method that is already widely used in IVF clinics, and is immediately applicable to humans. Here's what's even more beautiful about the technique: Anytime IVF is performed, you can create genetically identical ES cell lines from that blastocyst without the need for cloning via nuclear transfer. It is, at its basics, an organic form of cloning, much like twinning is just nature doing a cloning experiment, but because you are just isolating a cell from the inner mass, it can't generate trophectodermal cells and could never be implanted into a female, and thus has no potency for organismic life.

Does this mean that we can now go about making new human ES cell lines from discarded and cloned blastocysts? Hell no! Members of the President's Council of Bioethics have already refused to view a compromised blastocyst as a non-human life. They are devoutly opposed to any cloning experiments and are seeking efforts to criminalize current scientific pursuits. I consider it quite sad that the field of bioethics has been breached, compromised, and corrupted by neoconservatives. The true scientific leaders in both the bench science, and in analysis of science have been silenced and rendered impotent by the current administration, and the United States is flailing in the world stage in advancement of human stem cell technology. I await the official opposition to the above technique. It'll be a good laugh.

What I really love about these advancements is that we are going to reduce them down to their basic argument of god versus science. Their objections are no longer valid. We are happy to institute bans on reproductive cloning and are happy to develop new techniques that prevent the incapacitation of the blastocyst during ES cell isolation, unnecessary as it may be. We are happy to experimentally validate our ideas, while they hide and cower in their churches. They know that they are fighting a losing battle and have already dug their trenches while they await certain destruction. Sadly, their little squabble is going to cost in human life and in scientific advancement. But I'm confident that in the end, we will get our way and it will be good. After all, the purposes of therapeutic cloning and stem cell therapies is in the advancement of science and medicine. Yes, we may in the process also redefine what life is and when it begins, reaffirming abortion and reproductive rights, but the best part is that it will become a part of science and not philosophy or religion.

I'm sure someone really smart and literate like Pharyngula has already blogged about this to death, and I know that someone really smart and literate like Scott Gilbert is writing a whole book about bioethics, from the standpoint of real science. And I know that I will offend and mortify people with the above espousing. But it's my rant, and I feel better for having said it.