Experimental Subjects for Life?

More than a year after the birth announcement of genome-edited babies in China, we are only slightly more informed of He Jiankui’s experimentation, the results of which are named “Lulu” and “Nana.” Although apparently approached, neither Nature nor the Journal of the American Medical Association (JAMA) chose to publish He’s work. Antonio Regalado reported on an unpublished manuscript in “China’s CRISPR babies: Read exclusive excerpts from the unseen original research” in Technology Review on 3 December 2019. The Technology Review article includes not only excerpts of the manuscript from He, but also reactions from Stanford law professor Hank Greely; University of California—Berkeley’s gene-editing scientist Fyodor Urnov; the scientific director of Eugin assisted reproduction clinics, Rita Vassena; and reproductive endocrinologist Jeanne O’Brien, from Shady Grove Fertility.

Regalado summarizes some of the problems with Chinese experiment as follows:

 . . . key claims that He and his team made are not supported by the data; the      babies’ parents may have been under pressure to agree to join the experiment; the supposed medical benefits are dubious at best; and the researchers moved forward with creating living human beings before they fully understood the effects of the edits they had made.

Greely points out the lack of “independent evidence” of the claims made in the paper. Urnov labels the paper’s claim of reproducing the usual CCR5 variant “a deliberate falsehood,” and calls the statement about the possibility of millions being helped through embryo editing “equal parts delusional and outrageous.” O’Brien’s concerns include the possibility of coercion of the couples involved, and, noting the social stigma of HIV-positivity in China, she poses the question of whether this was a genetic fix for a social problem. Certainly, the Chinese experiment raises many questions, including how a culture views children. Are children gifts to be received or projects to be completed? Is it appropriate to subject children to experimental research because we can? One of the quotes from the paper reads, “we have made a follow-on plan to monitor the health of the twins for 18 years and hope to then reconsent for continued monitoring through adulthood.”

We would be remiss if we thought that China alone plans to remake humanity. Vassena is quoted regarding He’s study:

Unfortunately, it reads more like an experiment in search of a purpose, an    attempt to find a defensible reason to use CRISPR/Cas9 technology in human embryos at all costs, rather than a conscientious, carefully thought through, stepwise approach to editing the human genome for generations to come.  As the current scientific consensus indicates, the use of CRISPR/Cas9 in human embryos destined to give rise to a pregnancy is, at this stage, unjustified and unnecessary, and should not be pursued.

Vassena, who directs a fertility enterprise, it should be noted, appears comfortable with impacting the human genome for generations to come:  It just needs to be a “reflective” and “mindful” approach. That is chilling. Would she, or the study’s authors, or Greely, or Urnov, or O’Brien sign up to be a science experiment for the rest of their lives? I would not consent—not for myself nor for my children—no matter how “reflective” or “mindful” the researcher happened to be.

Finally, “Lulu” and “Nana” should be known as more than the results of someone’s laboratory experiment. They are human beings, not laboratory rats or cells under a microscope to be studied at the will and convenience of the experimenters.

Regulating New Technologies

History’s lessons applied to Artificial Intelligence (AI) regulation is the subject of a recent Brookings article by Tom Wheeler.  He writes

Societies impose government oversight for the protection of old principles in a time of new technology. Foremost among those principles is each individual’s right to a future; and it comes in multiple manifestations. In the educational realm, it means adequate training to be meaningfully employed. Economically, it means maintaining the benefits of capitalism through checks on its inherent incentive to excess.

Most importantly, the right to a future begins with the belief that there is a future, and that national leaders care about whether individuals affected by new technologies participate in that future.

Although the author has AI in mind, it is interesting to consider his words in relationship to the regulation of human gene editing. Now is certainly “a time of new technology,” particularly regarding human germline gene editing.  The “old principles” of experimentation on human research subjects ethically done and informed consent, along with the restrictions/bans in many countries heretofore prohibiting human germline modification, come to mind.  Additionally and importantly, in Greely’s extensive review of how “CRISPR’d babies” came to be, he includes a welcome overview of the state of affairs regarding regulation (or not) of human germline genome editing, in the October 2019 Journal of Law and the Biosciences. 

An upcoming meeting (London, November 14-5) of the International Commission on the Clinical Use of Human Germline Genome Editing is slated to discuss more than governance of the technology. Their agenda is available here.  In addition to a discussion of issues and perspectives relayed by various parties in their evidence submitted to the Commission, there is a planned discussion of “how the rights of future people have been considered and established in other medical and nonmedical scenarios, and how consenting to any necessary or preferred long term follow up on behalf of future generations could be established.”

Exactly how does one generation prescribe the “necessary or preferred long term follow up” of succeeding generations? How does one generation assure consent of future generations? When Wheeler penned the Brookings article about AI regulation (quoted above), he wrote about the right to a future, which rests in part on the fact that “national leaders care about whether individuals affected by new technologies participate in that future.” It certainly seems reasonable that those who are affected by a project be allowed to participate in it – as something more than research subjects. If such is true for AI, how much truer should it be for those whose very selves are affected by the research! There has to date been no compelling reason to go forward with human germline genome editing, and there are many reasons not to proceed. The most appropriate regulation is a ban.        

Failing the Grade in Transplant Ethics

On 3 October, ProPublica published “‘It’s Very Unethical’: Audio Shows Hospital Kept Vegetative Patient on Life Support to Boost Survival Rates,” an article detailing aspects of the organ transplantation program at Newark Beth Israel Medical Center in New Jersey. Specifically, the article revealed portions of an April 2019 audio recording from a weekly meeting of transplant physicians, nurses, social workers, and transplant coordinators. One patient discussed was a 61-year-old man named Darryl Young, who had received a heart transplant on 21 September 2018. Mr. Young had never awakened after surgery, but the director of the heart and lung transplant program, Dr. Mark Zucker, expressed the “need to keep him alive until June 30 at a minimum.” Another transplant surgeon hoped that the transplant program would progress to the point of not having to “think about this ethical dilemma of keeping somebody alive for the sake of the program.”

At issue—at least in the transplant realm—is the “need” of hospitals to keep patients alive for at least one year after organ transplantation.   Why? The Center for Medicare & Medicaid Services (CMS) dictates the rules for transplant centers to exist and to receive funding. Two measures CMS uses for this are the 12-month survival of patients and the functioning of the transplanted organs at 12 months (see page 6/84 of linked article).  The penalty for not meeting the desired CMS algorithms is high. CMS can launch an audit of the transplant program and/or revoke Medicare funding, which pays for the transplants. When programs are not funded, they cease to exist.

There are other issues in this story as well: ethical issues that deserve our best thinking. One glaring problem is that of treating people as means to an end, cogs in a wheel.   The case of Mr. Young is sadly exemplary, but he surely is not the only one. Pressure to maintain the transplant program will be felt by all of the participants in one way or another. Everyone is responsible for his or her actions, certainly, but each person downstream of a decision may well be used as a cog in a wheel. The penalties for non-compliance at different levels may be varied, but are no less real. Additionally, can patients, or their family members/surrogate decision makers, refuse any procedures once they are in the transplant system?

The current CMS rules were instituted on 28 June 2007. This 2006 article from the Los Angeles Times presents some of the backdrop for such rules:

  • Medicare, which funds most of the nation’s transplant centers, requires programs to perform a minimum number of transplants and to achieve a specific survival rate to be certified for funding. The benchmarks vary by organ, and there are none for kidney transplants.
  • Three dozen heart transplant programs didn’t meet federal standards for survival or volume. They accounted for 43 more deaths than expected.
  • Altogether, the programs examined by The Times had 71 more patients die than expected within a year of transplant.

It appears the 2007 rules represent a pendulum swing from 2006. A golden mean is desired and preferable. It is time to look for one.

Whose Body?

In 1923, Dorothy L. Sayers published her first mystery featuring Lord Peter Wimsey, entitled Whose Body?  The concern was that an adult body, wearing only a pince-nez, had been found in someone’s bathtub. Whose body was this? Was it the body of a well-known financier, who had recently disappeared? Or was it the body of someone else? Whose deceased body was this?

Slightly less than one hundred years later, the nation that Sayers called home has answered that question. As of Spring, 2020, in England, and a few months later in Scotland, deceased adult bodies are the State’s for purposes of organ procurement – unless they are in an “excluded group” or have registered an “opt out” decision.  The public is currently being assured that organ procurement will not apply to all who die, but only to those whose organs would be in a “usable condition”—primarily those dying in intensive care units or accident and emergency departments.

The law of “deemed consent” applies to all but these excluded groups:

  • Those under the age of 18
  • People who lack the mental capacity to understand the new arrangements and take the necessary action
  • Visitors to England, and those not living here voluntarily
  • People who have lived in England for less than 12 months before their death

The language of “deemed consent” is the iron fist in a velvet glove. According to the National Health Services’ FAQ page:

 If you have not recorded a decision either way and you are not in an      excluded group, your family will be approached and asked if they have any information about your organ donation decision. If no information is available, it will be considered that you consent to donate your organs and your family would be expected to support this.

Although the language of donation is used, gifts are what is “given.” To call what is “taken” or “coerced” a gift is to contort language into misrepresentation.

It is a conundrum the government is trying to solve. Every day, some people needing organ transplants die. Every day, some people with potentially transplantable organs die. Inviting people to decide whether or not they want to be organ donors, and register that decision, seems a reasonable step. But deciding that the government has the right to take organs upon death is overreach. Human organs are not property. We do not “own” our organs. Whether one views human beings as ensouled bodies or embodied souls, human organs are integral to those bodies.  The government did not give the people organs; it is an injustice – to the language and the people – to take human organs and call such “donations.”

Decrying Human Fetal Tissue Research Justification

The National Institutes of Health (NIH) released on 26 July “Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research.”  A new bullet point is required for “Human Fetal Tissue Research Approach.”   The applicant for funds is obliged to justify the use of human fetal tissue (HFT) in proposed research:

  • Why the research goals cannot be accomplished using an alternative to HFT?

  • What methods were used (e.g. literature review, preliminary data) to determine that alternatives could not be used?

  • Results from a literature review used to provide justifications

  • Plans for the treatment of HFT and the disposal of HFT when research is complete

  • Description of planned written, voluntary, informed consent process for cell/tissue donation, or description and documentation of process if cells/tissue were already obtained. Include a sample of the IRB approved consent form with the application or during the JIT process. The informed consent for use of HFT from elective abortion requires language that acknowledges informed consent for donation of HFT was obtained by someone other than the person who obtained the informed consent for abortion, occurred after the informed consent for abortion, and will not affect the method of abortion; no enticements, benefits, or financial incentives were used at any level of the process to incentivize abortion or the donation of HFT; and to be signed by both the woman and the person who obtains the informed consent. Include an assurance letter

  • Information must be submitted by the applicant Institution in a letter assuring the HFT donating organization or clinic adheres to the requirements of the informed consent process and documentation that HFT was not obtained or acquired for valuable consideration. . . . Applications proposing HFT research that do not include this assurance will be administratively withdrawn and not reviewed.

Journalist Nick Hazelrigg decried this as “Another Setback to Fetal Tissue Research Under Trump.”  Hazelrigg called the recently announced requirements for grant applications “the newest in a number of barriers . . . for fetal tissue researchers.” His first stated concern is that the applicant would have to “in a detailed manner, explain why no alternative methods could be used to accomplish the research.”  Secondly, Hazelrigg complains that both graduate and postdoctoral students who are supported by NIH training funds will be banned from using HFT in research.

Interestingly, on the same day the NIH released the new requirements regarding HFT research, the NIH Office of Laboratory Animal Welfare updated the “Vertebrate Animals Section” portion of their website.  Not only do grant applicants have to tell what kinds of procedures they plan for animals –inter alia, behavioral tests, blood draws, surgeries, and substance administration— but also justification for the use of animals is required.  Specifically:

Investigators must justify the use of animals in the proposed research. U.S. Government Principles require grantees to consider mathematical models, computer simulation, and in vitro biological systems. The justification should:

  • Indicate why the research goals cannot be accomplished using an alternative model (e.g., computational, human, invertebrate, in vitro).
  • Provide rationale for the choice of species (e.g., advantages of the species chosen and why alternative species are not appropriate).
  • Discuss why less highly evolved or simpler animal models are not appropriate. For example, the use of non-human primates, dogs, or cats should be thoroughly justified.

The justification for the number of animals, sex, ages, and other biological variables should be described in the Research Strategy.

We need to consider that the justification of use of resources is a common theme in human existence. Family members are accountable to one another for resources held in common. Business partners are also. When seeking a loan at a bank, the applicant has to justify the amount requested. These are true when only money is involved. When animal life is affected, the higher level of justification is rightly required. And when human life is involved, the highest level of justification should be demanded.

Restricting the use of human fetal tissue in research furnishes us all with the opportunity to consider our ways. In the words of Paul Ramsey, it gives us, the people,

final authority within constitutional limits in determining how in future we mean to be healed—when the means is human experimentation. The technical expertise of the medical research community cannot be the sole or chief arbiter in this matter, which is a question of morality and public policy.

(Ramsey, Paul. ”Introduction.” In The Ethics of Fetal Research, xxi. New Haven: Yale University Press, 1975.)

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.