Class 12 ethical issues related to stem cells What are stem cells?

1. Class 12 ethical issues related to stem cells What are stem cells? adult, lineage-specific (e.g. bone marrow-blood) embryonal, pluri-(or toti-)-potent What is differentiation? Where do embryonal stem cells (ESC) come from? blastocyst, inner cell mass, ~ day 5, before implantation in vitro fertilization (IVF)

2. Other sources of stem cells Fetal germ cell (sperm, egg) precursors Somatic cell nuclear transfer (SCNT) -> enucleated egg (cloning) Induced, pluripotent stem cells (iPSC) somatic (non-germ cell) cells, e.g. skin cell stimulated to de-differentiate using DNA or RNA or proteins involved in controlling differentiation

3. What are potential uses of stem cells? reproductive cloning cell therapy to replace damaged tissues e.g. after heart attack, spinal cord damage, Parkinson’s IF you can control differentiation how well can we control differentiation? are these likelihoods exaggerated? iPSC are most impressive example, but be skeptical…

4. What kinds of evidence suggest that some cells are pluripotent or totipotent? In vitro, or in animal (in vivo) expression of proteins typical of 3 “primary” developmental tissues (endo-, ecto-, meso-derm) Chimeras – mix black strain mouse ESC with white mouse strain embryo -> implant in utero -> pup has black/white coat (some cells from each set of parents); note DNA does NOT mix - cells keep their genetic identity. Breed chimeric pup with black mouse; if sperm/egg from chimera has “black” genotype, you get pure black strain offspring; this proves ESC were totipotent

5. What are ethical dilemmas? hESC come from embryos (or germinal ridge of aborted fetuses) Should a 5-day embryo be considered a human? When does life begin in a moral sense? Is it problematic to set a criterion, e.g. gamete fusion, implantation, formation of primitive streak, ability to feel, to think? Are these arbitrary, do they distinguish us from animals, are they too late?

6. Suppose you could treat gametes in way that precluded their development into embryo or fetus, but allowed them to form hESC… would this avoid the ethical problem? or is it a “gimmick” that relies on arbitrariness of “when life begins” definition? is it different from just deciding not to implant fertilized eggs?

7. Do many, even those with fairly absolutist views, implicitly recognize an intermediate status? e.g., those opposed to abortion except in case of rape; the fetus is not guilty, so rape does not justify its abortion; suggests the holder of this view views the fetus as not equivalent to a child Given lack of agreement, and strength of views, should governments seek a middle position, e.g. no taxpayer money for hESC research but allow it to be done privately?

8. What would Kant say? What is a Utilitarian view? What are views of different religious groups? Who’s interests are denied if you don’t allow government funding of stem cell research? Alta Charro’s view: don’t focus on unanswerable questions but on balancing political rights: the more intense the views of those opposed and the more limited their political options, the greater the likelihood of medical progress must be to justify government funding; => don’t hype

9. In vitro fertilization quandaries Multiple embryos usually created at once because of medical risks of collecting eggs ? impracticality of freezing-thawing eggs Non-implanted embryos are frozen What to do with unused embryos? Donate to another couple? Keep frozen indefinitely? Discard? Use for research?

10. If used for research, is this “using” a human being? Should it be the parents’ decision? If the sperm comes from an anonymous donor, should the mother be able to donote w/o father’s consent? Should the issue of donation be discussed only after a decision to destroy the embryo, to avoid biasing toward research use? Should IVF physician and researcher be different people to avoid conflict of interest?

11. Should it be illegal to pay for donation, to avoid financial inducement? Should the parent(s) have the right to limit use of resulting stem cells, e.g. for use of family members? Should parent(s) have the right to withdraw use of stem cells at some future date? Is it ok to create embryos by in vitro fertilization expressly for research, i.e. not as by-products of reproduction?

12. Should government funding for research use of hESC be more tightly regulated than private funding? Should there be limits to how long human embryos can be cultured in vitro – e.g. stop before development of primitive streak? Should reproductive cloning be illegal? Why? Should there be restrictions on mixing hESC with other species’ blastocysts and implanting in animal uteri to see how the hESC cells develop? Will animal studies like this be necess- ary for FDA approval of therapeutic hESC lines?

13. Bush era policy: I. No federal funding for research that involves destroying an embryo (Dickey-Wicker amend.) II. Federal funds canbe used to study hESC lines that were already in existence Is II unethical if you accept I? Is this analagous to: surgeons who transplant murder victims’ organs don’t condone murder; what if the donors were prisoners executed for capital crimes? Only ~ 20 hESC lines were in existence at that time, and many were patented. Is this a problem?

14. 2005 - National Academy of Science (NAS) Guidelines To provide guidelines for private sector and state government funded hESC research OK to create hESC for research alone provided fully informed, un-coerced consent, no monetary payment or other inducements, All parents must consent – so can’t use embryos with anonymous sperm donor OK to inject hESC into animals but no progeny animals can be bred out of concern that human germ cells might be produced

15. NAS Guidelines – cont’d Must set-up local ESC Research Oversight Committees - like IRBs - because some research involving hESCs escapes IRB review (hESCs are not considered human subjects) No reproductive cloning No injecting ESCs into human uteri No injecting hESCs into non-human primate uteri Not legally binding

16. 2009 - Obama relaxes some Bush restrictions Allow federally funded research on new hESC lines (derived without federal funds) All hESC used in federal research must have rigorously obtained parental consent Still no federal funding for creation of hESC (as this involves destroying embryos) No funding for SCNT experiments

17. Obama ironies – Some Bush era hESC lines did not have adequate consent documentation - so list of approved cell lines went down! 2010 – DC District Court Judge declared all NIH research on hESC illegal, on theory that it violates prohibition on destroying embryos (Dickey-Wicker amendment, passed every year since 1996 by foes of hESC research)

18. Do you agree with the District judge that you shouldn’t be able to use federal funds to study objects you can’t use federal funds to create? Even it Congress was fully aware of the ethical compromise and supported it? The Appeals Court ruled the NIH can continue to fund hESC research while the District Court’s decision is appealed

19. iPSCs – is this a way out of ethical quandaries? iPSC = pluripotent stem cells from somatic cells so no need to destroy an embryo Major scientific advance in terms of control of differentiation state First done by injecting 4 cancer-causing/ transcription regulatory genes; but injecting DNA -> mutation; eventually repeated by transient exposure to small # of proteins

20. But controversies: Do iPSCs have same broad differentiation potential as hESCs? iPSCs appear to have more mutations, epigenetic changes than hESCs What are cancer risks assoc. with stem-cell therapies, given close connection between de-differentiation and cancer?

21. Main points Technology challenges old ways of making distinctions in complex moral problems Tough to balance differing views when fundamental issues of life and reproduction are involved hESC are derived from ~5 day old embryos; they can differentiate into lots of tissues; they have promise (so far unrealized) for cell therapy of several diseases

22. US government has taken intermediate position allowing federal funding for research use but not creation of hESC lines, provided parents give informed consent This compromise has had Republican and Democratic support, but is being challenged in court; challenge could be “mooted” if Congress abolished Dickey-Wicker Private sector is freer to develop hESC; this work is subject to voluntary regulation