Sheldon Krimsky Lenore Stern Professor of Humanities & Social Sciences,

1. Genetically Designed Babies & Mitochondrial Disease Sheldon KrimskyLenore Stern Professor of Humanities & Social Sciences, Tufts University July 12, 2018 International Bioethics Summer School Hunter College, New York City

2. Historical Context Since the publication of Splicing Life in 1982, the report of a national bioethics advisory committee, there was a widely recognized moral principle preventing eugenics--transforming human beings through genetics. Introducing genes into a fully formed person—into their somatic cells was viewed as closer to drug therapy than genetically modifying sperm, egg or embryo.

3. Somatic Cell Germ Line Gene Therapy Gene Therapy MORAL BOUNDARY

4. “Zygote therapy would thus involve an alteration of the genetic inheritance of future generations and a significant departure from standard medical therapy.” (p. 46).

5. Weakening the moral boundary • As time progressed, some scientists and bioethicists began to question whether the restriction against genetically modifying babies --gametes/embryos was the correct ethical boundary.

6. A new proposal was introduced: The distinction became enhancement vs. therapy. In other words if the intervention was designed to “cure” or “repair” the gamete or embryo, that would be permissible; but if it were to enhance it, it would not. • The term was “enhancement eugenics”

7. Even that moral position did not hold. One journal editor and leader in the field of human gene therapy wrote: the real distinction should not be enhancement vs. therapy but whether the modification changes “our humanness.”

9. And some scientists, declared that there should be no barriers to transforming human beings—to create a new human through genetics.

10. Late 1990s: Ooplasmic Transfer in Women • Since the first IVF birth in England in 1978—Louise Brown, IVF has been one of the fastest growing assisted reproduction technologies in the world.

11. St Barnabas Medical Center, which goes back to 1865, houses the Institute for Reproductive Medicine & Science—considered one of the nation’s largest fertility centers. Dr. Jacques Cohen, an embryologist of the Institute, developed a technique in the 1990s called the cytoplasmic (or ooplasmic) transfer: the contents of a fertile egg from a donor are injected into the infertile egg of the patient who has undergone unsuccessful attempts of IVF along with the sperm.[

12. Cytoplasmic Transfer • Cytoplasmic Transfer : A technique in which cytoplasm from a donor egg is drawn into a pipette containing a single sperm from the male partner, after which that donated cytoplasm and the sperm are injected into the patient's egg.

13. Reasons for Cytoplasmic transfer • To improve chances of pregnancy—enhance fertility • To prevent the transfer of mitochondrial disease to the newborn. • (mitochondria generate ATP from food sources) • ATP= adenosine triphosphate; provides energy to cells

14. Mitochondrial Disease The mitochondria are cells in the cytoplasm—sometimes hundreds. Each cell has 37 genes compared to 20-30,000 in the cell’s nucleus.

15. Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support growth.

16. The mother might not be affected or may be mildly affected by mitochondria that are mutated—but the child born to her might be highly affected. • By transferring mitochondria from a donor cell to the mother’s cell, the good mitochondria can overwhelm the abnormal mitochondria. (the sour milk analogy).

17. First child born with ooplasmic transfer • In 1997, Cohen & Colleagues at St. Barnabas Hospital reported the first human pregnancy following cytoplasm transfer from donor oocytes into eggs of a patient with a history of fertility problems. • Levy & Yves, 2003.

18. The authors stated that “these are the first reported cases of germlinemtDNA genetic modification which have led to the inheritance of two mtDNA populations in the children resulting from ooplasmic transplantation.” Whether all these children are entirely healthy, however, remains unclear, and no follow up studies have been completed to verify the results.

19. The lack of testing and long -term follow-up of the children born from the procedure so far is a significant shortcoming, making evaluation of the safety and effectiveness of the technique very difficult.

20. FDA stops ooplasm transfer • Two babies at St. Barnabas had detectable mitochondrial DNA heteroplasmy—considered by many reproductive biologists as a risk factor for the offspring. • In 2001 a letter from FDA/DHHS went to IVF clinics and researchers: “We want to advise you that the [FDA] has jurisdiction over human cells used in therapy involving the transfer of genetic material by means other than the union pf gamete nuclei.” FDA cited ooplasm transfer as one of the examples.

21. FDA wrote: • “The use of such genetically manipulated cells (and/or their derivatives) in humans constitutes a clinical investigation and requires submission of an Investigational New Drug application (IND) to FDA”

22. Meanwhile other procedures for treating mitochondrial disease were being tested on animals. • While the FDA was considering the proposals on ooplasmic transfer, other procedures were developed to treat mitochondrial disease. • Oooplasmic transfer • Pronuclear Transfer (PNT) • Maternal Spindle Transfer (MST). • PNT & MST involve scooping up the nuclear DNA of the mtDNA-damaged egg and transplanting it to an enucleated donor egg. • What they all have in common is a three genome baby—two female mt genomes, 1 female nuclear genome and 1 male nuclear genome.

23. In the pro-nuclear transfer, you take the sperm and egg (fertilized) from intending parents. You extract two pronuclei; then you take a donor egg and sperm from intending father (fertilized). Remove pronuclei from donor egg. • Replace the pronuclei with that of intending parents. • Now you have an egg with healthy mitochondria. • In Material Spindle Transfer, the spindle (haploid chromosome) is removed from intending mother’s egg and transferred into an enucleated donor egg (spindle removed). Now the mother’s nuclear DNA is in an egg with healthy mitochondria. Intending father’s sperm fertilizes the egg.

27. ShoukhratMitalipov has developed a procedure to help women conceive without passing on their genetic defects. • Dr. Mitalipov’s (National Primate Center in Oregon) procedure would allow these women to bear children by placing the nucleus from the mother’s egg into a donor egg whose nucleus has been removed. The defective mitochondria, which float outside the nucleus in the egg’s cytoplasm, are left behind.

28. ShoukhratMitalipov, National Primate Center in Oregon

29. Two Reasons For & Three Reasons Against Gene Editing Human Embryos • 1. Healthy Children: Mitochondrial Disease Prevention • 2. Reproductive Autonomy • 1. Do No Harm: Risks of Gene Editing • 2. Social Issues: Social Disparities & Eugenics • 3. Violation of Basic Ethical Principle

30. 1. Healthy Children. A woman seeking to get pregnant has defective genes that will contribute to a seriously abnormal child, say with mitochondrial disease. She does not want to use a donated egg. In her case the selection of a healthy egg from her available eggs (preimplantation genetic selection) is not possible because all her eggs are effected with mutated mitochondrial DNA. Her only choice to have a child with her nuclear DNA is to allow gene editing of her embryo. Here choices to have a healthy child with her nuclear DNA are quite limited, unless gene editing of her egg or the early embryo is permitted.

31. Reproductive Autonomy According to this argument parents should be able to use whatever method or methods available to them which they are capable and willing to pay for to have a baby of their desire, with whatever traits, physical, intellectual or psychological, for either therapeutic repair or enhancement which they believe can be offered to them in their child. Governments should not dictate or set limits on their reproductive autonomy, the expression of which will not harm other people. This is a strong libertarian position on human reproduction and include personal eugenic choices.

32. Do No Harm: Risks of Gene Editing Creating a child by gene editing an embryo or sperm or egg is too risky and is more likely than not to produce damaged children with heritable traits. The human genome, or the genome of any living thing for that matter, is not a Lego system. In such a system if you add or subtract a part it does not affect the other parts. In contrast, the biological genome is an ecosystem. By targeting one gene you will more than likely affect other genes in the system.n The damage might not be expressed right away, but years later or even in another generation—the offspring of the targeted embryo.

33. If you genetically modify a plant or an animal and get a bad outcome, you simply discard the product. If you genetically modify a human embryo and get a bad outcome (genetically damaged) and you bring it to term someone will have to care for that child for life, either the parents or the government. In such a case the risks and costs to society outweigh the benefits to the parents for a so-called enhanced child. • We already have methods for eliminating the birth of a genetically damaged child by pre-implantation genetic screening. There are, however, a small number of cases where PGS will not work. That is where egg donation or adoption provide alternatives.

34. Concerns about 3-Genome Babies • Risks of heteroplasmy • Communication between nuclear and \ mt DNA • Beginnings of germ line gene modification

35. Mitochondrial heteroplasmy • “Infusion of 3rd party mitochondria itself or with deletions and/or mutations could theoretically increase the risk of mitochondrial heteroplasmy” (Chappel, Obst & GynInt2013). • “Metabolic abnormalities in offspring may have been due to the differences in response to nuclear signals between the two populations of mitochondrial DNA.” Chappel, Obst & GynInt, 2013).

36. Cytoplasmic transfer appears to be consistently associated with mitochondrial heteroplasmy (Scott and Alkani, 1998). • Heteroplasmy—or babies born with two distinct female mitochondrial genomes, is a risk which must be understood before cytoplasmic transfer aka ooplasm transfer is considered for clinical practice. • While an estimated 30 babies have been born using the technique there have been no systematic follow-up studies that examine the rate and degree of heteroplasmy in the newborn and in cases where it exists on its effect on the developmental health of the child.

37. Heteroplasmy created by the mixture of cytoplasm from different strains of mice resulted in physiological impairment, including disproportionate weight gain and cardiovascular system changes. • Cytoplasmic transfer used in cattle produces heteroplasmic offspring (Ferreira et al. 2010). • Some children born through cytoplasmic transfer have been identified as heteroplasmic (Levy et al. Human Reproduction 2004). • Mixing of two different mouse mitochondrial DNA within the same female germline can lead to offspring with neuro-psychiatric defects (Shapely et al. CELL 2012)..

38. “Mice show significantly altered basic physicological functions when in a heteroplasmic state.” • Ferrera et al Biol of Reprod, 2010 • “heteroplasmic animals had increased body mass and fat mass compared to controls at all ages…had abnormalities in electrolytes and hematologic parameters.” Acton et al. Biol of Reprod, 2007

39. “Cytoplasmic transfer is still an experimental technique that, while offering treatment to some infertile couples, is equally capable of generating unexpected abnormalities.” • St. John, Human Reproduction, 2002

40. “There are concerns that cytoplasmic transfer could cause major epigenetic modifications, and two of the first 16 pregnancies involving cytoplasmic transfer had chromosomal abnormalities.” • Brown et al, The Lancet, 2006

41. As for enhancement, most of the qualities parents might consider desirable for a genetically modified child involved a lot of genes. For example, it is estimated that 100,000 genes may be at work in establishing height, each gene making a very small contribution. • Suppose hypothetically, such an enhancement procedure can be proven safe and efficacious. Are there other reasons against it?

42. 2. Societal Issues Try to imagine that gene editing can improve the memory of a child. No one would argue that a good memory is not desirable and would not give someone benefits in school or a career. So for a certain sum of money some parents can endow their child with an advantage in life. It is highly unlikely that any current society, even those that have a higher welfare state, would make this available to everyone. So only certain wealthy families would be able to take advantage of this benefit. As a result, this technique would contribute to greater disparities in society. Those children born with this trait will be in an elite group and would be rewarded for it. Now it is true that wealth provides all sorts of benefits to children, including getting access to expensive elite colleges. But do we want to invest public funds in research to use genetics to create a genetic aristocracy.

43. There is no clear distinction between therapy and enhancement. Consider the experiment done by the Chinese scientist who genetically edited two female embryos. He believed he was engaged in therapy—preventing HIV infection. But under all accounts, the embryos were not genetically abnormal, so he was simply giving them an enhancement against infection. Just imagine that range of properties parents might choose for their embryo: height, skin color, memory, disease resistance, longevity, even intelligence. • Now we can also imagine the use of eugenics for diminishing humanity of people. How to create children who lack empathy because they may be more desirable as soldiers. Where ever we can imagine improving human qualities, we can also imagine diluting them for certain ends. A eugenics society is hardly something a just society should aspire to.

44. 3. Violation of Basic Ethical Principles. • Imagine a world where all societies were equitable with no economic disparities with universal healthcare. If everyone had equal access to genetic enhancement, and it were proven absolutely safe and should there be an occasional mistake, national health care would step up to the plate and take care of a genetically disable child for his/her entire life. • Would there still be a reason remaining for opposing gene editing? • There is an ethical principle that is widely accepted in all enlightened societies. “Treat persons not as a means to an end, but as an end in themselves.” • An embryo is not yet a person, so strictly speaking the ethical principle does not apply. But a corollary to the principle seems like a reasonable derivative.

45. The germ plasm of a person-to-be is the essence of what makes us human. • The Corollary: Do not treat the human germ plasm (the embryo) as a means to an end, but as an end in itself. • Attempting to genetically engineering an embryo for some enhancement trait violates the principle. Under those circumstances, the germ-plasm of the embryo is viewed purely instrumentally to achieve some end and is not respected as an end-in-itself as the nascent person. • But suppose society has strict regulations against the use of embryo editing for enhancement, rather only for correcting a genetically damaged embryo? Then would it be acceptable? Not unless there were a clear demarcation between therapy and enhancement. Also, there would be no way to police the demarcation.

46. Without a way to stop the cross-over to eugenics once you start human embryo editing, the corollary “Do not treat human germ plasm as a means to an end, but as an end it itself” should prevail precluding its use on human babies.

47. Questions to be answered • Is gene editing embryos safe and effective for the offspring? Can it ever be proven safe and effective? • If the procedure is found to be generally safe but with some risks, do prospective parents have the authority to undertake the procedure, balancing risks and benefits, without additional oversight. • Are the potential benefits of ooplasm transfer or gene editing for improving fertility or preventing the transfer of mitochondrial disease unique and sufficient to open the door to germ line genetic modification. What will be next—trying to make babies more intelligent?

48. International treaty on genetically modifying the human genome • Inheritable Genetic Modification (IGM) is prohibited by the Charter of Fundamental Rights of the European Union, the Council of Europe’s Oviedo Convention on Biomedicine and Human Rights, the United Nations Education, Scientific, and Cultural Organization’s Universal Declaration on the Human Genome and Human Rights, and other instruments of international law. Supported by 40 countries.

49. Reproductive Autonomy vs Communitarian Values • Maximizing one’s interest (libertarianism) • Maximizing the good of society (communitarianism). • Fulfilling an ethical principle independent of utilitarianism.

50. The End Questions?