Stem Cells: Ethical and Regulatory Issues April 10, 2013 Stem Cells: Ethical and Regulatory Issues Sidney H. Golub, Ph.D. Chair, UC Irvine Human Stem Cell Research Oversight Committee (hSCRO) Stem cell research is controversial and poorly understood. Given the profound therapeutic promise of this undertaking, it is important that the public, as well as the medical community, be aware of its scientific underpinning as well as the legislative hurdles faced by its advocates. A stem cell is one that can renew itself and give rise to specialized cells. Therefore, they have the potential, in the test tube, to become mature cells which can then be given to patients afflicted with diseases in which such cells are lacking or dysfunctional. Thus, the most important characteristic of various types of stem cells is their relative capacity to become various types of mature cells. This process is known as differentiation.

Proof that stem cells are of great public interest – several of the cover stories of national magazines.

Nobel Laureates 2012 John Gurdon Shinya Yamanaka

Stem Cells Make Copies of Themselves Through Cell Division, or … Stem cells are also good at multiplying. One batch can reproduce into billions more, which gives scientists enough stem cells to initiate the kind of tissue growth necessary for finding cures and treatments. On top of that, each cell is a copy of the original.

…Stem Cells Adapt for Many Parts of the Body Pancreas Brain Heart Bone marrow Fat Why is this important? Because biomedical researchers believe that mature, healthy cells created from stem cells can replace those in damaged tissue. This would be an important step toward conquering a great many debilitating conditions once regarded beyond the reach of medicine.

Pluripotent Stem Cell Sources Embryonic. Obtained from excess blastocysts from IVF procedures. Fetal. Obtained from miscarriages or abortions. Some promise shown in treating CNS diseases or injuries. Nuclear transfer to generate blastocysts. Same technology for reproductive cloning. Unsuccessful thus far in humans. Induced pluripotent stem cells (iPS) created by transferring about 4 genes into adult cells.

The blastocyst, a structure smaller than a pinhead, is the source of embryonic stem cells. Embryonic stem cells are removed from the blastocyst and grown in the laboratory to produce additional embryonic stem cells. Dominic Doyle

Human Blastocyst 0.1-0.2mm diameter. Day 4-5 post fertilization. Source: NIH website

hESC Ethical Issues Blastocysts as a potential human life “Respect” for fetal-embryonic materials Nuclear transfer technology raises the possibility of human reproductive cloning Research use of human-animal ‘chimeras’ might alter our definition of ‘human’ Defining the rights of the donors of the genetic material. Equitable use of stem cell products

Moral Status of the Embryo Utilitarian view (Bentham, J.S.Mill) Stem cells have the potential to create the “greatest good for the greatest number.” Uncertain fate of blastocysts. Promoting happiness is moral and curing disease produces happiness. Problem: Moral relativism? Deontological view: A matter of moral rules and duties (Kant) Every one has a right to expect not to be destroyed for the benefit of another. Embryos have these rights too. Therefore, destruction of an embryo is immoral. Problem: Are users of ESCs complicit?

Moral Status of the Embryo When Does an Individual Life Begin? At conception -- Roman Catholic view since Pope Pius IX in 1869, reinforced in 2008 by Vatican document "Dignitas Personae." Along with abortion, ESCs are a moral and political issue of importance to many Fundamentalist-Evangelical Protestants. Reliance on Biblical text. Many other religious views place beginning of personhood later Aristotle to Thomas Aquinas. “Quickening” as part of the Christian (Protestant) tradition. Islam and Judaism; traditional 40-120 days, respect for healing. Buddhism and Hinduism; reincarnation, karmic implications, sacrificial traditions, centrality of compassion.

Embryonic Stem Cells from Somatic Cell Nuclear Transfer (SCNT) If inner cell mass is placed in culture, the stem cells will divide Develops into a blastocyst Asexual production of pluripotent stem cells

Human Reproductive Cloning Opposed by the National Research Council as “dangerous and likely to fail.” Opposed by all reputable scientific organizations Already regulated by the FDA Bills twice passed House to ban research (criminal penalties) but died in Senate In contrast, human reproductive cloning is widely condemned. Indeed, it is opposed by all governments, the UN and all reputable scientific organizations. This includes the National Research Council, which is part of the National Academy of Sciences – a body that for more than 140 years has served as an independent and trusted science advisor to Congress and the nation.

SCNT Current Status Theoretical approach to custom design stem cell products and minimize rejection of transplants Works in rodents and large mammals (sheep, dogs) but not yet in humans Claims of SCNT success from South Korea now completely discounted as fraudulent Induced pluripotent stem cells largely supplant SCNT although successful cell fusion with oocyte reported (2011). Restore Homo neanderthalensis?

Nobel Prize Winning Experiments

Stem Cell to Gamete Nature 491:535-6, 2012 Nature 491:535-6, 2012

Chimeras: Myth or Mad Science? Etruscan chimera statue (Photo: National Geographic) Chimeras are organisms composed of stable combinations of cells derived from different species.

Chimera Issues Can human embryonic stem cells differentiated into brain cells and inserted into mouse brain make the mouse think like a human? Outcome If human stem cells were inserted into developing non-human embryo? Use non-human oocytes for human SCNT? L. Kass “The Wisdom of Repugnance.” Self-imposed rules: No breeding of recipient animals, No inter-species blastocysts.

hESC Ethical Issues Blastocysts as a potential human life “Respect” for fetal-embryonic materials Nuclear transfer technology raises the possibility of human reproductive cloning. Research use of human-animal ‘chimeras’ might alter our definition of ‘human’. Defining the rights of the donors of the genetic material.

Views of IVF Patients Lyerly and Faden, Science (2007) 317:46 1244 survey respondents 1020 with stored embryos Proportion likely to donate for: infertility research 63% disease or injury research 62% stem cell research (derivation) 60% to infertile couple 22% thaw and discard 22%

Stem Cell Professional Regulation Guidelines from National Academy of Sciences, ISSCR, other scientific groups California and other state standards Consensus on key points: Altruistic and consented donations of genetic materials Provenance of cells and tissues No reproductive cloning, no reproducing chimeras Local oversight (SCROs)

Current Federal Policy 1995 NIH appropriation amendment (Dickey-Wicker) prohibits federal funding to create or destroy human embryos for research. Renewed annually. Legal issues resolved. President G. W. Bush 2001 limitations on funding lifted by President Obama in 2009. NIH review process: 207 lines eligible for funding, 56 pending (3/2013). 2005 law promotes umbilical cord blood banking as an alternative to ESCs. Fetal cells allowed for transplants (1993). Sale of fetal/embryonic materials prohibited (2006).

Current Federal Policy Does NOT Affect: Legality of embryonic stem cell research Legality of research using somatic cell nuclear transfer Authority of states to expand, fund, limit or prohibit stem cell research Anything to do with IVF

States with permissive stem cell Legislation or Executive Orders WA OR ID WY NV CA $$$ UT AZ CO NM KA OK MO AR TX LA MS IL $ ND SD MN WI IA NE MI IN OH WV PA NY $$ VA KY VT NH ME CT $ MA $ RI NJ $$ DE MD $ NC TN AL GA SC FL HI AK States with permissive stem cell Legislation or Executive Orders States limiting research (criminal) on embryonic or fetal materials MT 2010

California Proposition 71: “Stem Cell Research and Cures Initiative” Authorizes $3 billion toward stem cell research (an annual spending limit of $350 million). Creates "California Institute for Regenerative Medicine." Establishes constitutional right to conduct stem cell research. Prohibits state funding of human reproductive cloning. Passed Nov. 2004 with 59% statewide, 52% in Orange County. $99.95 million to UCI thus far What else does Proposition 71 do? Along with allocating $3 billion toward stem cell research, it prohibits state funding toward human reproductive cloning. It also creates the California Institute for Regenerative Medicine, which regulates and funds state-sponsored stem cell research. And to make certain the state does its job, the proposition also creates a citizen’s oversight committee to govern the Institute.

UCI Human Stem Cell Research Oversight (hSCRO) Committee Appointed October 2005 9-10 members (stem cell science, clinical investigation, fertility medicine, ethics, science policy, community reps) Policy and scientific review. About 300 reviews so far, about a third were new. 36 ongoing. Coordinates with IRB, IACUC and other oversight bodies

UCI hSCRO: Issues Considered To Date Provenance of cell lines; original consent for donation of materials Use of pluripotent and differentiated human cell lines in animals Donation of blastocysts Donation of oocytes Parthenogenesis and SCNT Reprogramming of adult cells

The Sue & Bill Gross Stem-Cell Research Center at the University of California, Irvine UCI also hopes to house this center in a new building dedicated to stem cell research. This year, we announced plans to build a 52,000-square-foot facility to provide research and administrative space for our new stem cell research center. UCI believes a facility of this magnitude will create a cutting-edge environment for existing research and clinical initiatives on campus, as well as attract new biomedical researchers. Once funding is secured, campus planners estimate that it will take two years for the $50 million facility to become operational. Importantly, UCI’s Stem Cell Research Center will make space available to visiting faculty and members of the private sector, giving UC Irvine a unique opportunity to make Orange County a regional hub for stem cell research.