Human ES Cells for Huntington Disease – the Australian Way
By Ricki Lewis
Palm Springs – I’ve been hearing about stem cells at scientific meetings for nearly a decade – from the yearly International Society for Stem Cell Research meetings, to stem cell symposia at various large conferences, to focused events such as the New York Stem Cell Foundation meetings. But it is a poster at a meeting here in Palm Springs that really has excited me.
I’m at the annual meeting of the CHDI Foundation, which funds research to discover treatments for Huntington disease. This cruel illness begins in men and women in their prime, causing uncontrollable movements and sometimes cognitive decline. With the ruthless pattern of autosomal dominant inheritance, children watch affected parents and other older relatives slowly lose control, knowing that this may be their own, or their children’s, future. Genetic testing can identify “pre-manifest” individuals who have inherited the mutation, and there is no cure – despite the House episode in which a patient jerks and the snarky doc barks, “Order a genetic test! Start the Huntington’s meds!”
The poster I’m drawn to is on a square of neat white fabric in the corner of the exhibition room. It lacks the complex biochemical pathways and clever experiments of the other posters, but instead quietly describes the potential of stem cell research with this one powerful example – Huntington disease.
The author, Tomas Stojanov, PhD, explains how Sydney IVF has obtained human embryonic stem cells that have the Huntington’s mutation from “extra” embryos that couples undergoing IVF have donated. The human research ethics committee of the National Health and Medical Research Council approved the culturing of the embryos for legally defined embryos that are “excess” to the couple’s reproductive needs or intentions. The decision did not affect their treatment, they weren’t paid, and their private information and identity were kept confidential.
Obtaining hES cells requires in vitro fertilization (IVF) followed by pre-implantation genetic diagnosis (PGD), which tests a cell of an 8-celled embryo for a family’s mutation. If it isn’t there, the remaining 7-celled embryo can be implanted in the woman. If not, it can be discarded – or studied. Nurturing it into an embryo is technically not possible and ethically too disturbing, evoking images of the pickled fetuses in Brave New World. But letting development go far enough to collect inner cell mass cells, which can then be cultured to yield ES cells, can be a tremendous boon to basic research. That is actually the goal of most hES cell research, not the therapeutic applications that the media and politicians trumpet.
These HD hES cells, which will be available to researchers in a few months, will make it possible to chronicle the earliest hints of the disease by supplying cocktails of the appropriate growth factors to steer specialization towards neural progenitors and, ultimately, the neurons that accumulate intractable tracts of the amino acid glutamine in the disease. Global gene expression profiling can reveal effects on all other genes, painting portraits of the pathology that have never before been seen, which hopefully will reveal new drug targets. Most exciting is the coming use of inducible genetic controls that enable researchers to activate the mutant gene at any time, so that what is growing in cell culture can mimic what is happening in a person in the decades before those first telltale movements begin.
The HD hES cells promise a degree of mimicry that is not possible with the much-promoted induced pluripotent stem cells. Read the papers on the iPS cells and you’ll find qualifiers galore ‘– “essentially identical” to ES cells; “almost identical,” “behave like,” and “similar to.” Dumping four biochemical factors onto skin fibroblasts is simply not the same as starting from scratch to watch a disease develop in tissue culture.
What researchers find from the Sydney hES HD cells, and from similar efforts at a handful of universities, will complement ongoing studies to catalog the earliest signs of HD – the unusual eye movements, changes in gait, and even altered facial expression that some clinicians say reveal who has inherited the family legacy.
Thousands of families worldwide are living with Huntington disease. A few hundred early embryos – not fetuses, not babies stuffed into test tubes as President Bush imagines, but the deceptively unremarkable inner cell mass cells that become ES cells – can illuminate the disease process in a way never before seen. Multiply that by the many other diseases whose underpinnings we do not understand, and it is clear that it is unethical to not allow this research. Where’s the controversy?
Ricki Lewis is a fellow at the Alden March Bioethics Institute and a geneticist. She has just published “Stem Cell Symphony,” a novel about HD, stem cells, iPods, and U2. Check it out on amazon.com.
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"babies stuffed into test tubes as President Bush imagines"
Was this necessary? Can you point to anything President Bush has said that indicates he thinks babies are being stuffed into test tubes?
If you regard anyone whose opinion you don't share with such contempt, no wonder you don't see the controversy.
- by Laura(southernxyl) on Feb 7, 2008 at 1:48 PM | link
I apologize if I offended you. I meant no harm, but I have an opinion too. President Bush on numerous occasions, by his choice of words, has indicated that he is not aware of the extent of development of a blastocyst. "Stuffing babies into test tubes" was hyperbole. I thought that was obvious, but I guess not.
- by Ricki Lewis on Feb 8, 2008 at 2:54 AM | link
Ricki, I'm not sure he is not aware of the extent of development of a blastocyst, either.
Many people, me included, consider that life - that is, human life worthy of respect and protection - begins at conception. To explain this as briefly as possible, when I wanted to reach a conclusion about this, I thought that I needed to find a bright line between life/not life. I can't see acknowledging that an individual is a living human but that his life is without value if his death would be convenient for another individual. Fetal development occurs on a continuum. If one picks out an event such as the heart beginning to beat, (a) it doesn't immediately start beating the way a mature heart does, and (b) different individuals will hit that milestone at different times; you can't say "X happens at Y weeks" and cover every individual. You can see this by looking at premature babies. Some born at 30 weeks aren't ready and can't be saved, others do very well and later have no averse effects. So the trimester divisions don't make much sense either if you're looking for life/not life or viability. Birth isn't really a bright line either, which was confirmed for me when my daughter was born 3 weeks before her due date. That would have been 3 weeks that she was a human, when if I hadn't gone into labor early she would have been an amorphous clump of cells (bit of hyperbole there.) But going back all the way to ova and sperm, each gamete has the potential to become an infinite variety of humans depending on which gamete it finds to join with; or nothing at all if conception doesn't happen to occur. Once conception occurs, a unique individual exists who did not exist before. So there is my bright line. Some people think implantation is the magic moment, which makes a certain amount of sense because it's known that many, perhaps most, embryos don't implant, so it looks like "nature" views them as throwaways. I see that but it's not compelling to me. So for me, conception is it.
The point is, you absolutely do not have to agree with me. I will not think you are stupid or misinformed if you do not. On the other hand, the fact that I have this view that most likely differs from yours doesn't make me stupid or misinformed. If I skimmed your article and thought, "she doesn't care about helping sick people, she just wants any excuse to keep abortion legal" I would be wronging you, for one thing, but also denying myself an opportunity to check my conclusions and make sure they are still valid; something we should all do from time to time.
- by Laura(southernxyl) on Feb 9, 2008 at 9:59 AM | link
Hi, Laura. I do understand and respect your viewpoint, more than you may believe. I spend many hours a week as a hospice volunteer, and my daughter too was born early, at 4 pounds. Having written biology textbooks for a quarter of a century I know very well the stages of development -- I've even shown a collection of human embryos and fetuses, real ones, to my students as I discuss development, so they can see what I am describing. I do see your view. But as far as stem cell research goes, at the inner cell mass stage, they are undifferentiated cells. They haven't even formed layers yet, let alone the beginnings of a heart. It is the proverbial slippery slope. Within every cell (except erythrocytes) lies a genome that given proper prodding could become a human individual. So where do you draw the line? Ban all of cell biology? My opinion is that some of those cells -- most especially those that would otherwise be thrown out, horrible thought -- be used to help the many millions of people who must live with devastating illness -- like the man with ALS whom I spend many hours with a week. If you thought that I am either heartless or stupid you would be very mistaken. With my post I only meant to inform on a topic that would otherwise have not have made it into the news. The families with Huntington disease and other conditions that the media tends to ignore crave research news. But you're right in that I should have left Bush out of it. Ricki
- by Ricki Lewis on Feb 15, 2008 at 5:35 PM | link
Dear Ricki,
I've read your article with interest. I currently study biochemistry at Oxford, UK, and recently got interested in bioethics and this sort of things.
Regarding Laura's views, I must say I sympathize with them. People often say that conception is not a good moment to choose, as it only results in genome being formed and, well, genome is found in almost every cell of the organism. But you must admit that there is something special about conception - the genome made is somewhat unique and is most likely to become an individual (or identical twins). If we value our uniqueness, which to quite big extent rises from our genome being different than genomes of all other people (except identical twins once again), you must admit that a newly formed zygote is somewhat different than just any somatic cell. And also if you go back to see what was at the beginning of life of each human being, it is this single cell - so it is somewhat special once again (this reverse perspective helps to grasp it, I think). So I would point out to these two things: uniqueness of zygote and to potentiality of it becoming a certain individual (before it there is nothing that we can treat as a potential individual, if we assume cloning is morally unacceptable), as two reasons for conception being treated as something special.
But still I think you could consider zygotes as not as "fully human" as a child or an adult - well, it is a "spark of humanity", the beginning of it, and it may go on to becomeing a fully human person, with its own story, with its own human life. And although this spark is very important, probably second most important after a human being itself - maybe there is some space for discussion about possibility to use zygotes for research in some extreme cases - where research is very likely to be successful and the benefits are very big. But my view in such a discussion would be against use of zygotes. But I would listen to other views of course.
The problem with argument about using zygotes for research which may help to cure disease is that people who are in favor of such a use can always use the trump card of "it is only a cell, and it may help to save many people". But this utilitarian argument is a slippery slope, I think, although I believe that people using it are really empathic and want the best for other people. Say we can choose one human, and make experiments on him, which will help to cure all the diseases there are - you have a full organism on which you can test whatever you want, so it may be used well, you must admit. But surely we wouldn't allow it, because it IS a human being, and we do not normally consider utilitarism being more important than human life. Now consider an ill and dying person - can we use him? Also not. Consider a newborn infant - can we use it for an experiment - also not. Can we use a person in a coma? - also not. But for all this example you could use the same utilitarian argument, e.g. in the last case it would be: it is only a person in a coma, most likely he will not wake up, so why not use him for research? Anybody's answer would be: not because it is a human being. And if somebody is giving the same answer to the use of zygotes, I think it is fair enough - there is more in being human than just looking like a human being, or having many cells, or feeling - being human also means having unique genome, having potential to become something, being formed as a result of love - this are all things which also are characteristic of human beings. Ethics are not a thing which you can approach fully rationally, because if you want to be rational, I really don't think there's any really rational argument against killing even a grown-up person, especially if he is of ill health, if many people may benefit from it.
- by Marcin on Feb 19, 2008 at 6:07 PM | link
Ricki,
I think you have laid out a very compelling argument to embrace this embryonic stem cell research and learn everything we can from it. Thanks.
Dad taught high school biology for 40 years. Last year he was diagnosed with Huntington's disease. The doctors are pretty sure I have it too. He and I spend a lot of time following the research. Unfortunately we seem to be much better at treating mice with genetic problems then we are at treating people.
As you know HD is caused by a single bad gene. As people with HD age they tend to develop some Alzheimer's like and some Parkinson's like symptoms. The difference is that HD has a very specific genetic cause. The population of people affected is relatively small (as is the R & D budget). We do not want it to get lost in the politics that have grown-up around the embryonic stem cell research debate.
We need to empower our doctors to be as comfortable working with human embryo's as they are with those of mice. It is amazing to me that we can take a mouse embryo and actually change the DNA so the mouse develops HD.
If a couple is going through IVF and find their embryo has any genetic problems and the couple is not going to use it they should be encouraged to donate the embryo to science. Let us leverage these unfortunate situations as an opportunity to learn. We as a country really should be driving this effort.
Ultimately if a couple finds out they have an embryo with a genetic problem we want to fix the embryo so the couple can go ahead and have their baby. And we don't want them to have to leave the country to get this done. This is for our children's children. We will not get there if we keep our heads in the sand about the embryonic stem cell research.
Ricki, Thanks again. I think what you are doing is great.
- by Dave Hess on Feb 24, 2008 at 7:53 PM | link