Embryonic Legerdemain?

Developmental biologist Lewis Wolpert is credited with saying, “It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life.” Gastrulation, simply put, means the embryo develops an axis and distinctly different cell layers. In the human embryo, gastrulation takes place during the third week post-fertilization. Formation of endoderm occurs over days 14-15, and the mesoderm begins to appear on day 16 (see Figure 1-11 here).  Ali Brivanlou, of New York’s Rockefeller University, identifies gastrulation, or the breaking of symmetry in the embryo, as the “major Holy Grail of developmental biology.”

Why is this so? During the third week after conception, the embryo has burrowed into the mother’s womb, and the peering eyes of scientists cannot visualize the events there. With the 14-day rule in place regarding embryo research, laws or guidelines in various locales outlaw or discourage (as in, do not fund) laboratory culturing of embryos beyond that point. So, Brivanlou’s lab “came up with a model of human embryos that is developed outside of the womb and is not the product of sperm and eggs, but the product of human embryonic stem cells that self-organize into complicated structures.”  These embryonic stem cells have formed what appears to be an embryo, but in Brivanlou’s terms, “could never become a baby.”

Dehumanizing the embryo is one of the essential components of making research on embryonic humans more palatable to the public. It will also be en essential step in a workaround of the 14-day rule. It appears that “model embryo” will join other terms such as “embryoids,” “gastruloids,” and “SHEEFs” as some element of humanity that scientists do not recognize as humans worthy of legal protection. Regarding Brivanlou’s “model embryo,” Harvard Medical School’s Dean George Daley calls it a “remarkable tool in a petri dish.” The “tool” with which Brivanlou and others concern themselves is both human and alive; otherwise, would they be interested?

Let’s think about this, using an analogue. If well-trained scientists could produce men and women without chests, what would be allowed? Would they have to call such men and women without chests “human”? Could they use men and women without chests for experiments?  Would the experiments have to be approved by institutional review boards?  Would the rest of us pay the scientists – handsomely – to do this? Could they win prizes?

Proposed moratorium on human germline: Asilomar analogue?

The Editorial Board of The Washington Post (WaPo) recently published their opinion  on regulation of heritable genetic changes in human eggs, sperm, and embryos. The authors expressed some measure of relief that organizations such as the National Academies in the U.S., the Royal Society in Britain, and the World Health Organization are beginning to consider the daunting topic of human heritable genetic changes. The board advised, “The goal must be a framework that will enable genuine scientific advancement but avoid reckless fiddling with the source code of life.”

The WaPo editorial board further recommended “something of similar scope and power” to that of the Asilomar Conference on Recombinant DNA Molecules, held in February 1975. Asilomar, as that conference came to be called, was convened to evaluate the risks posed by the novel technology of genetically modifying organisms. The public perception of Asilomar has been primarily one of scientists shouldering the “social responsibility of science.”

Further, the WaPo article pointed out that one of the authors of the March 2019 Nature commentary calling for a “global, temporary moratorium on clinical uses of human germline editing” was Paul Berg, a Nobel laureate, and one of the organizers of the Asilomar conference. The Nature commentary, authored by Eric Lander, Françoise Baylis, Feng Zhang, Emmanuelle Charpentier, and Paul Berg, described the consensus for a moratorium thusly:

The 18 signatories of this call include scientists and ethicists who are citizens of 7 countries. Many of us have been involved in the gene-editing field by developing and applying the technology, organizing and speaking at international summits, serving on national advisory committees and studying the ethical issues raised.

This description appears to differ substantively from one Berg gave of the Asilomar analogue. In an 18 June 2011 video interview by Larry Goldstein, Berg had this to say about the success of Asilomar:

We made some decisions that were smart in retrospect. For example, one of the things we did not do – and did not include in any way in the agenda was the ethics. We didn’t talk about genetic testing… we talked about real experiments, and what the impact of those experiments would be in the field (10:40-10:58)

Of the five authors calling for a moratorium on human heritable genetic changes, only Françoise Baylis is an ethicist. A 2004 article penned by Baylis and Jason Scott Robert, “The Inevitability of Genetic Enhancement Technologies,” gives insight to her views. The paper concludes with

. . . we maintain that accepting the inevitability of genetic enhancement technologies is an important and necessary step forward in the ethical debate about the development and use of such technologies. We need to change the lens through which we perceive, and therefore approach, the prospect of enhancing humans genetically. In recognising the futility of trying to stop these technologies, we can usefully direct our energies to a systematic analysis of the appropriate scope of their use. The goal of such a project would be to influence how the technologies will be developed, and the individual, social, cultural, political, economic, ecological, and evolutionary ends the technologies should serve. It is to these tasks that bioethical attention must now fully turn.

It appears that 1) Paul Berg’s previous concerns about “ethics” being involved is not a problem to date in this enterprise; and 2) the called-for moratorium is truly only a “speed bump” on the road to converting future generations into our own laboratory experiments. The “individual” ends such experiments will serve are likely to be the individuals who are paid handsomely to do such experiments or who hold the patents to the processes utilized – not the individuals formed. Despite the extensive embrace of heritable human genome editing by the principals cited here, we need to remember that this is not a road that we must travel. Future generations are not our playground. We need to rethink this “moratorium”:  It should be an outright ban.

Physician-assisted suicide, euthanasia, and the World Medical Association

The World Medical Association (WMA) is cogitating on physician-assisted suicide. Their current statement, adopted in 1992, “editorially revised” in 2005, and reaffirmed in 2015, is as follows:

Physician-assisted suicide, like euthanasia, is unethical and must be condemned by the medical profession. Where the assistance of the physician is intentionally and deliberately directed at enabling an individual to end his or her own life, the physician acts unethically. However the right to decline medical treatment is a basic right of the patient and the physician does not act unethically even if respecting such a wish results in the death of the patient.

WMA’s statement on euthanasia, adopted in 2002, and reaffirmed with minor revision in 2013, states

BE IT RESOLVED that:

The World Medical Association reaffirms its strong belief that euthanasia is in conflict with basic ethical principles of medical practice, and

The World Medical Association strongly encourages all National Medical Associations and physicians to refrain from participating in euthanasia, even if national law allows it or decriminalizes it under certain conditions.

Drama has been unfolding in recent months regarding these positions of the WMA. In October 2018, the Royal Dutch Medical Association (KNMG) and the Canadian Medical Association (CMA) together proposed that the WMA change its position to “neutrality.” This Proposed WMA Reconsideration of the Statement on Euthanasia and Physician Assisted Dying was retracted late in the process due to strong opposition.  The German Medical Association proposed a compromise of changes in the language. Those changes included “physician-assisted death” instead of “physician-assisted suicide,” and “physicians should not engage” in place of “unethical and should be condemned.”

The WMA decided to seek written opinions, and revisit the subject at the 2019 Council meeting. In a press release from 29 April 2019, the WMA Council announced that

It was agreed that policy work should continue on physician assisted suicide, augmented intelligence, violence against healthcare professionals and the patient-physician relationship.

With the next WMA Council and General Assembly scheduled for 23-26 October 2019 in Tbilisi, Georgia, observers should note the jockeying for position by various medical associations. It seems unlikely that those medical associations in jurisdictions where physician-assisted suicide or euthanasia are embraced would decrease pressure on the WMA. Yet we can hope that the World Medical Association will not succumb to such forces. After all, the WMA was formed in the shadow of World War II – a time when the raw wounds of incredibly inhuman acts by some humans against others had been recently seared into the minds of millions. The WMA needs to stay the course they set in 1946, for, to paraphrase George Santayana, those who do not learn from history are condemned to repeat it.

Biobags for extreme prematurity?

The newsfeeds have been abuzz this week about premature lambs gestated in part in biobags by researchers at The Children’s Hospital of Philadelphia. See “An extra-uterine system to physiologically support the extreme premature lamb” here.  The lamb has provided a model for much of our understanding of fetal and neonatal development in humans (see articles here and here for examples).  Therefore, the news of a method to gestate fetal lambs ex utero for up to four weeks generated a good amount of excitement.

The “single most important cause of death in the first month of life” for human infants is prematurity.  “About one percent of all infants” born in the U. S. are premature according to Dr. Alan Flake (video here).  Extreme prematurity in human infants is defined as less than 28 weeks gestational age.

Especially challenging is the plight of infants born at 23-24 weeks, and this is the focus of the research by the Children’s Hospital of Philadelphia group, according to the video at Nature World News. Fetal surgeon Flake describes the biobag as “a ‘bridge’ between the womb and the outside world.”

Application of the biobag technology to humans is on the horizon, but not yet available. The goals of the Philadelphia group appear laudable. There are often, however, unintended consequences of technology development. One potential possibility appears at the end of the discussion in the Nature article:

Finally, our system offers an intriguing experimental model for addressing fundamental questions regarding the role of the mother and placenta in fetal development. Long-term physiologic maintenance of a fetus amputated from the maternal–placental axis has now been achieved, making it possible to study the relative contribution of this organ to fetal maturation.

The role of the mother in fetal human development cannot be wholly replicated by the experience of the ewe and the fetal sheep. Could “amputating” the fetal human from his/her maternal-placental axis (i.e., mother) become a casual affair, or be done in order to study the effects of such amputation?  Could this “therapy” eventually become a “reproductive choice”? That is, once the procedure is available, could parents choose ectogenesis over in utero somatogenesis?

 

— D. Joy Riley, M.D., M.A., is executive director of The Tennessee Center for Bioethics & Culture.

Greetings and celebrations

and why there is no bioethics posting today . . .

My Muslim friends recently celebrated the Persian New Year with many symbols of spring. My Jewish friends are in the midst of Passover celebration. Today, Christians celebrate the Resurrection of Jesus Christ, and I am numbered among them.

Happy Spring! Happy Passover! Easter Blessings!

D. Joy Riley, M.D., M.A.

Surrogacy in the Market of Desire

The State of Florida has spilled no small quantity of ink outlining the legal confines of gestational surrogacy (see particularly sections 742.13-742.17, here).  Legally permitted gestational surrogacy in Florida does not include “bringing in and harboring aliens, sex trafficking of children, forced labor and furthering slave traffic,” however; these charges were leveled against Esthela Clark in 2015. Clark had held a Mexican woman in her one-bedroom apartment, repeatedly inseminating her with semen from Clark’s boyfriend. When the woman failed to become pregnant, she was forced to have sex with two strangers, and placed on a diet restricted to beans.  On 29 March 2017, the 47-year-old Clark from Jacksonville, FL, pled guilty to one count of forced labor. The woman had been forced to clean Clark’s apartment. (See story here.)  What happened to the issues surrounding the smuggling of the woman across the border in order to be a surrogate for Clark and her boyfriend?

On the other side of the globe, India is arguably the world’s leading provider of surrogate mothers, with the industry estimated several years ago as “likely worth $500 million to $2.3 billion.”  India legalized surrogacy in 2002, and is now considering reining in its surrogacy situation:

     The Surrogacy (Regulation) Bill, 2016

 

  • The Surrogacy (Regulation) Bill, 2016 was introduced by Minister of Health and Family Welfare, Mr. J. P. Nadda in Lok Sabha on November 21, 2016.  The Bill defines surrogacy as a practice where a woman gives birth to a child for an intending couple and agrees to hand over the child after the birth to the intending couple.
  • Regulation of surrogacy:  The Bill prohibits commercial surrogacy, but allows altruistic surrogacy.  Altruistic surrogacy involves no monetary compensation to the surrogate mother other than the medical expenses and insurance coverage during the pregnancy.  Commercial surrogacy includes surrogacy or its related procedures undertaken for a monetary benefit or reward (in cash or kind) exceeding the basic medical expenses and insurance coverage.
  • Purposes for which surrogacy is permitted:  Surrogacy is permitted when it is, (i) for intending couples who suffer from proven infertility; and (ii) altruistic; and (iii) not for commercial purposes; and (iv) not for producing children for sale, prostitution or other forms of exploitation.

In their 2012 Journal of Medical Ethics article, Deonandan, Green and van Beinum formulate eight “Ethical concerns for maternal surrogacy and reproductive tourism

Robustness of informed consent

Custody rights

Quality of surrogate care

Limits of surrogate care

Remuneration

Multiple embryo transfers and abortion

Medical advocacy

Exploitation of the poor

Of the eight ethical concerns Deonandan et al found in the Indian experience of surrogacy, at least five of them were present in the Florida case described above –and that would-be surrogate was not even pregnant! It seems that India is not the only entity that should reconsider commercial surrogacy.

 

— D. Joy Riley, M.D., M.A., is executive director of The Tennessee Center for Bioethics & Culture.

The Semantics of Therapy, Part II

A previous blog post of “The Semantics of Therapy” posed three questions about the human genome being a “patient” to be treated. One reader found the post “provocative and disturbing” and called for further explanation and discussion of the questions posed. That will take some time and several postings.

The first of the questions to be considered is this: If the “patient” is a genome, to whom does the researcher answer?   An answer from recent history may shed some light on this important issue.

33 infertile couples underwent a novel procedure at New Jersey’s Saint Barnabas Medical Center during the years 1996-2001. Embryologist Jacques Cohen used cytoplasmic transfer–ooplasm from the oocytes of fertile women was transferred into the eggs of infertile women–in the hope of establishing pregnancies in the latter. The outcome was 13 pregnancies and 17 babies from the Saint Barnabas experience (see accounts here and here).

According to a 2014 BBC article, one resulting pregnancy, which ended in miscarriage, revealed a missing X chromosome in the fetus. The same anomaly was noted in another child: one of a set of twins from a different pregnancy. Later, one child showed evidence of developmental delay. In 2014, Cohen estimated that the worldwide experience of cytoplasmic transfer between oocytes had resulted in the births of 30-50 babies, although the FDA had effectively stopped the procedure in the U.S. in 2002.

What had the follow-up on the babies born through cytoplasmic transfer been in 2014?

Due to a lack of funding, Cohen says, it hasn’t been possible to find out about how any of the children like Alana who were born from cytoplasmic transfer are doing. But the St Barnabus Institute is now starting a follow up study to check their progress (BBC).

In October 2016, Chen, et al, published “A limited survey-based uncontrolled follow-up study of children born after ooplasmic transplantation in a single centre,” in Reproductive BioMedicine Online.  Twelve of thirteen couples responded; parents of quadruplets did not:  “One couple disclosed the use of egg donor to their child. One reported intention to disclose; six were undecided and four reported they would not disclose.” (Article here.)

This admittedly biased study and a few newspaper-based profiles appear to constitute the follow-up of significant genetic intervention in babies-turned-human-subjects. So what will the future hold?

The recent committee report on human genome editing had this to say about heritable genome editing:

As with any new procedure, carefully monitored clinical trial protocols would be required for germline genome editing, with attention to monitoring off-target events as well as the efficiency and correctness of the specific edit. Unlike conventional clinical trials, germline genome editing trials would likely require long-term prospective follow-up studies across subsequent generations. This follow-up would entail study of the future children affected by the intervention, none of whom would have been party to the initial decision to participate in a research trial. . . . Even those who have volunteered to be research subjects cannot be compelled to participate in long-term follow-up. Nonetheless, encouragement is permitted. . . . (download available here)

Should we be comforted by the “long-term prospective follow-up” and the permitted “encouragement” that may be necessary?  Presumably the long-term prospective follow-up will be dependent upon the monies allocated for same (when the money runs out, so does the interest?).  When the State is involved, what kind of “encouragement” might be involved?

On the other hand, what about any anomalies that may be caused by these procedures?  Will pregnant women be “encouraged” to abort such offspring?  If born, will the resulting children be treated, or only followed like any other long-term science experiment?  Who explains to these, and indeed, all of the children born through germline genome editing, that they are indeed long-term experiments?

 

— D. Joy Riley, M.D., M.A., is executive director of The Tennessee Center for Bioethics & Culture.

A Conflict of Interest is NOT an Ambiguity

Oregon Senate Bill 494 has been described as a “euthanasia bill” that is “intentionally ambiguous,” and as a piece of legislation that would “allow the starving and dehydrating of patients who suffer from dementia or mental illness.”

What has received less press is the composition of the 13-member committee who would be perpetually in charge of advance directive forms in the state, with no oversight by the legislature. Who would those persons be? According to the bill, the 13-member “Advance Directive Rules Adoption Committee” would include

  • The Long Term Care Ombudsman or that individual’s designee
  • 12 members appointed by the Governor
    1. one representative of primary health care providers
    2. one who represents hospitals
    3. one clinical ethicist affiliated with a health care facility
    4. two health care providers with palliative care or hospice expertise
    5. one who represents persons with disabilities
    6. one who represents “consumers of health care services”
    7. one who represents “the long term care community”
    8. one who has expertise in “advising or assisting consumers with end-of-life decisions”
    9. three members from among those proposed by the Oregon State Bar:
      • an expert in elder law
      • an expert in estate planning
      • an expert in health law

Why is the State of Oregon so interested in making sure their appointees are in charge of advance directives?  Is it because the state is so concerned about the health of its citizens?  Hardly, when those citizens in the health care system are described not as patients, but consumers.  Stacking the committee with lawyers who are experts in estate planning and elder and health law seems to assure the state that they will get their pound of flesh.  The State is aware of this:  deceased consumers no longer need their money or their organs.  The conflict of interest inherent in this scheme is not ambiguous.

 

— D. Joy Riley, M.D., M.A., is executive director of The Tennessee Center for Bioethics & Culture.

Excuse Me, Doctor, What Exactly Do You Profess?

The late Edmund Pellegrino, M.D., revered medical educator, ethicist, and physician, often made the point that a professional professes something. Merriam-Webster  confirms that the etymology of the word, profession, includes the Latin for “public declaration.”

The Hippocratic Oath, probably penned by members of the Pythagorean sect, according to Ludwig Edelstein (see Ancient Medicine: Selected Papers of Ludwig Edelstein. Baltimore: Johns Hopkins University Press, 1987), has for centuries been accepted as the gold standard for the practice of medicine. Nigel M. deS. Cameron (The New Medicine: Life and Death After Hippocrates. Chicago: Bioethics Press, 2001)
 explicates the Hippocratic Oath as containing four parts:

1.   Covenant with Apollo and others

2.   Duties to teacher

                            Regard teacher as equal to parent

                            Treat him as a partner in livelihood

                            Share money with him when needed

                            Consider his children as siblings

                            Teach medicine to own children, children of teacher, and pupils who take the oath

3.  Duties to patients

                            Use treatment to help the sick, never to injure or wrong them

                            Give no poison to anyone though asked to do so, nor suggest such a plan

                            Give no pessary to cause abortion

                            In purity and in holiness to guard the practitioner’s life and art

                            Use no knife on “sufferers from stone,” but allow others trained to do so

                            Enter houses to help the sick, not to participate in wrong doing or harm

                            Keep oneself from fornication with woman or man, slave or free

                            Not to divulge, but guard as holy secrets those things that are heard by the practitioner

4.  Sanction

Oath-taking by medical students has increased in the last 50 years, as reported by Neil Chesanow, in “Is it time to retire the Hippocratic Oath?” Medscape, 25 Jan 2017.  The form of oath taken by medical students has also changed. Many schools have re-written the oath in “updated” language, and a good number of students craft their own.

Do they swear not to have sex with their patients? Do the medical students or newly minted physicians now swear not to give poisons or pessaries? What oaths are taken in those states where physician-assisted suicide has been made legal? It would be good for the public to know. Perhaps it is time for physicians to post on their walls (actual and virtual) exactly what it is they profess to be and to do.

 

— D. Joy Riley, M.D., M.A., is executive director of The Tennessee Center for Bioethics & Culture.

 

The Semantics of Therapy

What is therapy? This is one question that should occur to the reader of Jill Neimark’s “Unexpected Risks Found In Replacing DNA To Prevent Inherited Disorders.” In referring to the birth of the baby born of three parents last year, the author names it “mitochondrial replacement therapy”:

Using a technique called mitochondrial replacement therapy, the researchers combined DNA from two women and one man to bypass the defect and produce a healthy baby boy — one with, quite literally, three genetic parents.

Jill Neimark is not alone in this use of the term. Shoukhrat Mitalipov, who has lobbied several nations for funding for such research, and his co-author, Don P. Wolf, make that claim in their 2014 paper, “Clinical and Ethical Implications of Mitochondrial Gene Transfer.” Mitalipov and Wolf state that because the changes produced by mitochondrial replacement techniques are “permanent” and “would be transmitted through generations,” this qualifies as “germline gene therapy.” Therapy, according to the Oxford Dictionary of English, is “treatment intended to relieve or heal a disorder;” its Greek roots mean “healing” and “minister to, treat medically.”

Who, then, is treated therapeutically in “mitochondrial replacement therapy”? Is it the child? When John Zhang formed in the laboratory five embryos, each from three progenitors, only one embryo was transferred to a woman’s uterus. That child, a boy, was born in 2016. Readers are not told the disposition of four of the embryos that were not “normal.” If they were destroyed, one could not say that the mitochondrial replacement was for them therapeutic. If the child born of three parents lives a “normal” life, was the mitochondrial replacement therapeutic for him? From a scientific point of view, no, for he did not exist prior to his conception.

It appears, then, that the beneficiary of the mitochondrial replacement “therapy” is the genome. If this is true, a host of difficulties present themselves. Three of these are

  1. If the “patient” is a genome, to whom does the researcher answer?
  2. What other interventions in the genome will be needed? Who decides? Is there a limit?
  3. If the mitochondrial genome of a child so conceived reverts to that of his nuclear-genome-mother, as Mitalipov in his December, 2016, Nature letter reports as a possibility, then what recourse is possible?

— D. Joy Riley, M.D., M.A., is executive director of The Tennessee Center for Bioethics & Culture.