Is the United States Effectively Advancing Adult Stem Cell Research

1. Is the United States Effectively Advancing Adult Stem Cell Research? Disclosures Alan Moy MD Director of John Paul II Stem Cell Research Institute Founder and CEO of Cellular Engineering Technologies Inc. Pulmonary Associates of Iowa City Adjunct Faculty, College of Engineering, University of Iowa

2. Overview of stem cell biology. Terminologies Stem Cell: a). Self-renewal and b). Differentiate into a specialized cells (progenitors). Embryonic stem cells (includes cloning) - produce over 200 specialized cells but controversial, tumor forming, genetically unstable. Adult stem cells Inducible pluripotent stem cells.

3. Stem Cell Applications Preclinical tools for screening pharmaceutical drugs. Only therapy with broad spectrum applications. Cost and limitations of organ transplantation. FDA supported adult stem cell vs embryonic stem cell trials. Only stem cells have the potential to repair, regenerate and cure diseased tissues. Heart disease. Juvenile Diabetes Pulmonary diseases Blood disorders Cancer Rheumatologic disorders Neurological disorders Countermeasures for chemical, biological and nuclear threats. Pandemic infectious diseases.

4. Ethical Alternative to Cloning and Embryonic Stem Cells- Inducible Pluripotent Stem Cells (iPS) Process that reprograms adult cells (e.g. skin cells) back into an embryonic-like pluripotent stem cell. Ethical advantage - does not require destroying an embryo to create stem cells. Advantages over embryonic destructive research: ethically non-controversial, develop patient-specific PS and more cost effective.

5. Hurdles in Stem Cell Therapeutics Access to therapies in US. Experimental. Which stem cell to use? Timing of treatment? Patient selection? Require large dose of cells (0.5-1 million cells/lb body weight) Very significant regulatory manufacturing requirements imposed by the FDA. Animal safety and efficacy data - FDA requirement. Who pays? (3rd party payers are not going to pay for experimental therapy until clearly documented efficacious and safe).

6. Pro-Life Movement and Stem Cell Research Pro-life community is losing the war on stem cell research. US losing in the field of regenerative medicine. Secular scientific community overly promoting ESCR. Secular scientific community has framed the debate quite successfully by promoting cures for patients with ESCR. ESCR supporters using arbitrary bioethics. Pro-life strategy is educational/political advocacy without alternative. Stem cell research deficient in Catholic Universities. Using religious arguments NOT effective with government, politicians and academia. Pro-life movement need to understand human subject research laws and policies.

7. Historical Roots of Human Subject Research On December 9, 1946, an American military tribunal against 23 leading German physicians for crimes against humanity (USA vs Karl Brandt or Doctor Trial). German physicians planned “Euthanasia Program,” the systematic killing of those they deemed "unworthy of life." victims included the mentally retarded, the institutionalized mentally ill, and the disabled. German physicians conducted: pseudoscientific medical experiments on concentration camp prisoners without their consent. Most died or were permanently crippled (victims were Jews, Poles, Russians and Gypsies). Sixteen of the doctors found guilty and seven executed.

8. Pre-Nazi Era Prevalent culture of euthanasia - life that is unworthy of living. Over 140,000 people died in German psychiatric asylums as a result of hunger, disease or neglect during WWI. With National Socialists to power, two developments were promptly codified into law. sterilization program authorized euthanasia. German academicians and philosophers touted: those suffering from illness represented a restriction of the individual and capacity to perform in society. society had the the right to kill a suffering individual because society had more rights than the individual. couched in terms of "compassion" and "relief" from one's suffering. The record shows that it was in academics in the Third Reich that eager recruits were found and the concept of lives unworthy of life and its deliberate pursuit began there.

9. Nuremberg Code Free and voluntary consent of the human subject is absolutely essential. Informed consent of benefits and risks. The experiment should yield fruitful results for the good of society and not obtainable by other means and not unnecessary. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease. The experiment should avoid all unnecessary physical and mental suffering and injury or death. Omitted was any language about protecting vulnerable groups and human subject rights trump the benefit to society

10. Declaration of Helsinki of 1964 World Medical Association adopted guiding principles for conducting human subject research. The physician must be free to use a new diagnostic and therapeutic measure, if it offers hope of saving life, re-establishing health or alleviating suffering. It is the duty of the physician to remain the protector of the life and health of that person on whom biomedical research is being carried out. The subjects should be volunteers. The investigator or the investigating team should discontinue the research if in his/her or their judgment it may, if continued, be harmful to the individual. The interest of science and society should never take precedence over considerations related to the well-being of the subject. No specific emphasis on protecting vulnerable groups.

11. Henry Beecher Report Prominent academician and anesthesiologist. Published an article “Ethics and Clinical Research” in the June 16, 1966 issue of the New England Journal of Medicine exposing many clinical research trials that had been funded by the government that were very highly unethical. He gave 22 examples of unethical research. Example was that mentally retarded children at a state school were infected with hepatitis virus. PI felt that he was justified because a cure for hepatitis would help many more people. Beecher cited other clinical trials done on marginal members of society such as the poor, developmentally disabled and senile who couldn’t decide to participate in these trials. In July 1966 NIH called for an independent Institutional Review Board (IRB) to review all human subject research. Shortly after the FDA created rules for obtaining informed consent of investigations of new medicines.

12. Tuskegee Syphilis Study The study was conducted by the United States Public Health Service (1932-1972) to examine the long term affects of syphilis. The subjects of the study were 400 African American males who were primarily poor sharecroppers. These men all had syphilis, but were unaware of it. The most horrifying aspect of the experiment was in the 1950 penicillin was proved to be effective at curing syphilis. The researchers did not treat the men’s syphilis and even prevented other doctors who saw the participants from treating the syphilis. As many as one hundred men died from complications from their untreated syphilis. The project was shut down in 1972.

13. National Research Act National Research Act (1974) which created the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, which created a set of guidelines for conducting ethical human research. 1. Respect for Persons. Individuals should treated as autonomous agents Persons with diminished autonomy are entitled to protection. 2. Beneficence. Do not harm Maximize possible benefits and minimize harm. 3. Justice. Who receives the benefits of research and bear its burdens? An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. It also states that individuals with a lower capacity for making decisions, such as children, the elderly and the developmentally disabled needed special protection.

14. History of Human Embryo Research During the Reagan-Bush years (1980-1992) no non-therapeutic research using IVF-bred human embryos and no IVF research was governmentally subsidized. An Ethics Advisory Board was required by law to approve any such grant, and no such permission was given. The Ethics Advisory Board was allowed to go out of existence and no new appointees were named.

15. Concept of Pre-Embryo There has been a movement over the past 25 years to redefine the definition of an embryo and the beginning of life. Classical embryology defined the beginning at the point of fertilization between egg and sperm. The American Fertility Society (AFS) and the American College of Obstetrics and Gynecology have reinvented human embryology over past 15 years. In 1979, Clifford Grobstein, Ph.D., a developmental biologist, created a new term, the "preembryo” specifically to cut it off from the moral concern. Grobstein and the Reverend Richard McCormick S.J. formed an Ethics Committee of the AFS in 1986, which reaffirmed statements removing a moral status and protection of the conceptus up to 14 days post-fertilization.

16. NIH Revitalization Act of 1993 Senator Edward Kennedy, Massachusetts, and Representative Henry Waxman, California, pushed and helped enact the NIH Revitalization Act of 1993. Overturned the existing Ethics Advisory Board approval requirement and allowed the NIH to appoint a Human Embryo Research Panel "to provide advice as to those areas acceptable for Federal Funding".

17. Panel Recommendations Create human embryos as research objects. Removal of ovaries from brain-dead women and aborted fetuses so eggs (ova) can be recovered for laboratory fertilization and manipulation. Testing a panoply of drugs on the developing human embryo. Use of human embryos to create specific cell lines. Freeze and save as potential "spare embryos". Tests on human embryos for developing new lines of contraception. Fusion of animal specie cells or DNA fragments with human embryos. President Clinton announced that no federal funds would be used to fund the creation of research embryos, because of the great moral implications. But, he said nothing about spare embryos.

18. Federal Timelines After Roe v. Wade, Congress limited federal funding on human fetuses. 1995 Dickey-Wicker Amendment in 1995 prohibits Federal appropriations to fund research that creates human embryos for research. President Bush creates executive order prohibiting federal funding using ES cell lines created after Aug 9, 2001. President Bush issued Executive order 13435 to expand stem cell research to include non-embryonic stem cell sources. Executive order did not have specific funding commitments. 2009 President Obama rescinds the ES cell lines restrictions and executive order 13435.

19. Human Subject Research, ESCR and Cloning- Has Bioethics Advanced? Parallels include lack of informed consent, deliberate harm, and a devaluation of personhood to justify arguments that society benefits are greater than individual rights. Government is applying a double standard bioethics. How do we address the issue about experimentation on “spare embryos” and the argument that they are going to be discarded? Analogous to experiments in concentration camps, prisoners on death row or terminally ill patients (“they’re going to die anyway” argument). Should spare embryos be legal (illegal in Europe)? Do not discard IVF embryos. If one believes that life begins at conception, then ESCR violates prior codes and laws in human subject research. Diverse bioethical positions based on culture, religious beliefs, ect. Lack of formal bioethical training in secular academic institutions. Federal government has systematically moved bioethics away from a pro-life bioethics and one consistent with strict adherence to current human subject rules.

20. How Much Adult Stem Research Is Federally Funded? Bias against adult stem cell research. NIH funds > 300 embryonic stem cell projects compared to 80 adult mesenchymal stem cells, 5 amniotic stem cells and 0 cord blood derived multipotent stem cells. Much of the preclinical adult stem cell research milestones are being conducted overseas. Many of the cutting-edge regenerative medicine trials using adult stem cells are conducted overseas. There is far more regulatory burden in the US.

21. Breakdown of NIH Stem Cell Funding Less than 1% NIH budget devoted to adult stem cell research Annual growth for human embryonic stem cell is 2x that of human adult stem cell research (10 years HESC>HASC) Annual growth for animal embryonic stem cells is greater than human adult stem cell research. More funding for animal non-embryonic stem cell research than human non-embryonic stem cell research.

22. US Support for Adult Stem Cell Research Catholic Universities do not have the scientific infrastructures and expertise to conduct translational adult stem cell research. No private research foundation makes adult stem cell research a strategic priority. Private investors are apprehensive about investing because of intellectual property and political challenges. Scientists, media and politicians encourage bias against adult stem cell research despite the fact that adult stem cells have greater proof of concept and better safety record. Academia is quite poor in developing therapies. Academic primary focus is publication and not on therapies.

23. Foreign Adult Stem Cell Companies 1997 - 5 percent of companies were foreign 2005 - 46 percent of companies are foreign

24. Scientific Requirements Needed By The FDA Human adult stem cells produced under good manufacturing practice (GMP) standards-very expensive. Scale up adult stem cell production. Demonstrate safety and efficacy in animal models of disease. Phase I Clinical Trial - demonstrate safety in small patient groups. Phase II - Demonstrate efficacy and safety in small patient groups. Phase III -Demonstrate efficacy and safety in larger patient groups.

25. Good Manufacturing Practice (GMP)

26. Summary of Adult Stem Cell Research in US Inadequate financial support from government, private sector, industry, states and academia. Academic centers are are not devoting enough resources to ASCR. Academic centers are not training students in bioethics. US is not training enough young scientists in ASCR. There is an inadequate amount of ASC clinical research from academic centers and non-profits. Lack of private support toward ASCR.

27. John Paul II Stem Cell Research Institute (JP2SRI) Stem cell therapies requires a long-term horizon and ROI. Filed non-profit 501 (c ) (3) with Iowa Sec. State. Nonprofit, nonsectarian organization for charitable, educational and research purposes in stem cell biology. Pro-life stem cell research - adult, cord blood and placenta sources and iPS - DOES NOT conduct human embryonic stem cell or cloning research. Mission to lower barriers to advance adult stem cell treatments by creating partnerships between JP2SRI-academia-industry and private practice. Pursue solicited research to achieve scientific milestones for FDA approval.

28. JP2SRI MISSION Develop regenerative medicine therapies. Oversee and conduct preclinical and clinical FDA-directed adult stem cell research. Train other scientists in adult stem cell research and in bioethics Train clinicians on regenerative medicine therapies so they can take the skills back and treat their patients in their communities under a clinical research consortium.

29. CANCER RESEARCH A strategic priority for the Institute. Cancer results from a cancerous stem cell. Address personalized cancer treatment and diagnosis. Develop technologies that make cancer treatment more targeted and safer.

30. ORPHAN DISEASE RESEARCH 5000-8000 orphan diseases. 80 percent genetically based Challenges finding effective treatments: low patient numbers, market size, limited animal models. Potential solution: patient and disease-specific stem cells for drug screening purposes.

31. Question Which of the below institutions facilitated the largest repository of adult stem cells in the world for biomedical research? A). California Regenerative Medicine Institute. B). National Institute of Health. C). Oxford D). Pfizer E). All of the above. F). None of the above.

32. Milestones of JP2SRI to Date

33. Cellular Engineering Technologies, CET JP2SRI instrumental is coordinating patient recruitment and tissue procurement. CET, a private biotech company located at Oakdale, manufactures commercial adult stem cells for research market. In 2 years created the largest commercial supply of adult stem cells and progenitors (GLP). Developing normal and patient/disease-specific iPS cells. Do not conduct embryonic stem cell research or cloning. Products sold around the world to academia and pharmaceutical companies. Not approved for therapy or clinical research.

34. Human Adipose Mesenchymal Stem Cells – Applications of Various Differentiation Media

35. Conversion to Neural Progenitor Cells Human embryonic stem cell conversion into neural progenitors is inefficient and takes 3 weeks. Adult stem cell conversion into neural progenitors more efficient and occurs within 24 hours.

36. Inducible Pluripotent Stem Cells (iPS) Reprogramming adult human cells by genetic reprogramming via exogeneous expression of pluripotent transcriptional factors Produce embryonic-like pluripotent stem cells without ethical controversy and yield patient and disease-specific stem cells.

37. Conversion to Cardiac Progenitors Conversion of pluripotent stem cells into cardiac progenitors. Exhibit automaticity and contractility.

38. Institute and CET Develop Patient-Specific Somatic Stem Cells In December of 2008, the Institute helped Peyton Hadley, 11, and his sister, Kayla, 8, who both have Niemann-Pick Type C, a rare and fatal neurodegenerative disease due to cholesterol processing disturbance. Harvested and grew tens of millions of their stem cells from a teaspoon of their fat within 2 weeks. Used by scientists in Canada and NIH to screen drugs that may control Niemann-Pick Type C disease. Cell model of dementia and atherosclerosis.

39. Capital Campaign to Build the John Paul II Stem Cell Research Institute Proposal to create a 16,000 square foot facility at the BioVenture in Coralville, IA. Will house small number modular wet lab space, small scale GMP facility, small scale microfabrication laboratory, small animal laboratory facility, administrative offices and clinical treatment rooms. Estimated startup cost is:~10 million Estimated five year cost is:~ 30 million.

40. JP2SRI Poised to Address the Hurdles in Stem Cell Therapeutics JP2SRI is singularly poised to develop the most comprehensive adult stem cell program. 3 cord blood-derived stem cells. 1 cord tissue stem cell. 2 placenta-derived stem cell. Bone marrow-derived stem cell. Fat derived stem cell. Progenitor cells (liver, nerve, muscle, bone, cartilage, fat). Predict that JP2SRI will be one of the leaders in iPS technology. Private, academic and industry relationships in place. Animal safety and efficacy data - FDA requirement. Academic collaborations. Capital not science is the rate limiting problem.

42. Value of JP2SRI to Iowa Research Center for regenerative medicine cancer treatments orphan disease Economic development Advance status and expertise of hospitals.

43. Value of JP2SRI Globally Expand consortium in adult stem cell research. Lower the barriers of applied research. Return high public investment to society.

44. Educational Mission Objectives Advance adult stem cell research in academia. Increase the work force of adult stem cell scientists. Advance pro-life bioethics. Execution Plan Train academic faculty, postdoctoral fellows and students in adult stem cell research and bioethics. Provide sabbatical opportunities for academic faculty. Provide out-reach opportunities for undergraduate and graduate students in adult stem cell research and bioethics (e.g. internships and fellowships).

45. Strategic Plan Principles ASCR needs to be systematically well organized on a national level. Pro-life individuals need to be active participant in science rather than be bystanders. While we can still advocate our pro-life position, we’re going to have to find common ground between both political parties - looking to find cures and treatments for patients. Science and economics, not political advocacy, will determine the end.

46. Catholic Challenge Catholics/America are losing the battle on ASCR. ASCR is woefully under funded-HHS report indicated US government needs to invest over 2 billion dollars. Embryonic stem cell research community have successfully framed the debate as helping patients-pro-life. Embryonic stem cell scientific community has a monopoly on influence in government and in the media. Catholics are never going to change NIH agenda and secular academia. Catholics have restricted effort to educational advocacy without a constructive alternative (e.g. missions, pregnancy crisis centers, churches, schools and hospitals). Not a critical mass of adult stem cell researchers in US. Catholics have to take ownership of this issue- financially support adult stem cell research and offer alternative to ESCR: examples