rendering of luminous DNA with gene being removed with forceps.

Mainstreaming Reproductive Genetic Innovation

By Myrisha S. Lewis

Despite religious and ethical objections, assisted reproductive technology (ART), including in vitro fertilization and egg freezing, manages to flourish in the United States, with some states and companies even creating regimes for its insurance coverage. However, reproductive genetic innovation — a term I use to refer to the combination of assisted reproduction with genetic modification or substitution — has yet to receive the same acceptance. Examples of reproductive genetic innovation include mitochondrial transfer, cytoplasmic transfer, and germline gene editing.

Moreover, while many scientists, regulators, and members of the public have called for societal discourse or consensus related to individual reproductive genetic innovation techniques, these calls rarely include an explanation as to how these discourses would be conducted. In a recent article, Normalizing Reproductive Genetic Innovation, I offer four potential avenues for structuring a societal discourse in the U.S. on the topic.

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Doctor or surgeon with organ transport after organ donation for surgery in front of the clinic in protective clothing.

Pig Hearts for Humans and the FDA

By Jacob Balamut

David Bennett, a man who recently underwent the world’s first successful xenotransplantation organ surgery, died last month after a sudden and as yet unexplained period of rapid deterioration.

Bennett, who was 57 years old, had been suffering from end-stage heart disease. With limited options for treatment, he underwent an experimental emergency procedure to replace his damaged heart with a genetically modified pig’s heart. The pig was genetically modified to limit the likelihood that Bennett’s immune system would reject the heart.

Many researchers and clinicians alike see the potential for genetically modified animal organs to serve as a solution to our organ transplant and supply issues. The Health Resources and Services Administration estimates that 17 people die per day on the candidate waiting list. These deaths are the result of a lack of supply of organs, which has been a longstanding issue within the United States.

However, currently, the U.S. Food and Drug Administration (FDA) has not approved any genetically modified or pure animal organs for xenotransplantation in humans. For the surgery to go forward in Bennett’s case, the team had to submit a request to the FDA seeking to use the pig heart in the emergency procedure (so-called “compassionate use”). The lack of approved xenotransplantation products stems from a lack of safety data and concerns regarding the potential for cross-species infections to occur.

In 2016, the FDA updated previously existing guidance for xenotransplantation. The purpose of the guidance was to inform the industry of how the FDA would be handling xenotransplantation applications and to provide recommendations.  In order for xenotransplantation products to be approved, the following process must occur.

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Scientist analyzes DNA gel used in genetics, forensics, drug discovery, biology and medicine

Transplant Genomics: Ethical, Legal, and Social Implications

By Tamar Schiff

The appeal of precision medicine is of particular significance in transplantation. Treatment options are already integrally dependent on genetic factors – the donor-recipient match – and the demand for transplantable tissues far outstrips the available supply.

And the potential is only growing. Advances in genetic and genomic studies have identified an increasing number of novel biomarkers of potential use in transplant-related care. These include predictors of disease course, graft survival, response to immunosuppression, and likelihood of disease recurrence or other complications.

With wider availability of sequencing technologies and innovations in databanking, future clinical applications in transplant care may require ever-growing considerations of the significance of genetic variants, fair access to precision medicine therapeutics and participation in research, ethical approaches to data aggregation, and social determinants of health.

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Hands close-up of surgeons holding medical instruments.

COVID-19 and Organ Transplantation

By James W. Lytle

After a banner year for organ transplantation in the United States in 2019, the success became a tattered memory by April 2020, when the COVID-19 pandemic hit major cities in the U.S. with its full fury.

A record number of 39,178 organs were donated in 2019, including 7,397 organs from living donors, also an all-time high.  After several years of adverse media and regulatory scrutiny, LiveOn NY, the organ procurement organization (OPO) that serves the Metropolitan New York City region, proudly reported that a total of 938 organs had been transplanted in 2019, another record that represented more than a fifty percent increase over the transplant total in 2015.

By late April 2020, however, organ transplantation activity in New York State had reportedly declined by ninety percent.

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Undocumented Organ Transplants

By Brad Segal

Manuel—not his real name—was admitted to the hospital with decompensated heart failure. As a child he had scarlet fever which, left untreated, had caused the valves of his heart to calcify and stiffen. Over time, pumping against increased resistance, his heart’s contractions began to weaken until finally, they lost all synchrony and the normal function of his heart spiraled out of control. At this stage, his fate was tied to whether or not he would receive a new heart in time.

He was in his 30’s and had no other illnesses. From a medical perspective, Manuel was the ideal candidate for a cardiac transplant. But a decade ago Manuel crossed the United States border in pursuit of a better life. As an undocumented immigrant, he was ineligible for the insurance coverage necessary to pay for a heart transplant. After being thoroughly evaluated by the hospital’s transplant center, given his modest financial resources and inability to obtain new insurance coverage, Manuel was not placed on the waiting list for a new heart.

The average heart transplant costs about a million dollars to perform. Subsequent follow-up care adds another $30,000 annually. Health insurance will usually cover most, if not all, of these costs. But uninsured patients are kept off transplant lists on the grounds that the inability to pay for care allegedly jeopardizes an organ’s long-term success. Read More

Chimeras with benefits? Transplants from bioengineered human/pig donors

By Brad Segal

In January of this year, Cell published a study modestly titled, Interspecies Chimerism with Mammalian Pluripotent Stem Cells. It reports success bioengineering a mostly-pig partly-human embryo. One day before, Nature published a report that scientists had grown (for lack of a better word) a functioning genetically-mouse pancreas within the body of a genetically-modified rat. The latest study raises the likelihood that before long, it will also be scientifically possible to grow human organs within bioengineered pigs.

The implications for transplantation are tremendous. But hold the applause for now. Imagine a chimera with a brain made up of human neurons which expressed human genes. Would organ procurement without consent be okay? That troubling possibility raises  questions about whether manufacturing chimeras with human-like properties for organs is even appropriate in the first place. Here’s what University of Montreal bioethicist Vardit Ravitsky told the Washington Post:

“I think the point of these papers is sort of a proof of principle, showing that what researchers intend to achieve with human-non-human chimeras might be possible … The more you can show that it stands to produce something that will actually save lives … the more we can demonstrate that the benefit is real, tangible and probable — overall it shifts the scale of risk-benefit assessment, potentially in favor of pursuing research and away from those concerns that are more philosophical and conceptual.”

I respectfully disagree. Saving more lives, of course, is good. Basic science is also valuable – even more so if it might translate to the bedside. This line of research, though, is positioned to upend our entire system of transplantation, and so its implications go beyond organ supply. In this post I will argue that to assess this technology’s implications for organ procurement in particular, there is good reason to focus on harms, not benefits. Read More

Organs and Overdoses (Part II): ‘Higher risk’ donors

By Brad Segal

In my last post I characterized how overdoses from the surging opioid epidemic have become the fastest-growing cause of mortality among organ donors. In this update, I raise one potential consequence with ethical and policy implications: so-called donor-derived infections. To be clear, I focus primarily on organ recipients as deaths from drug overdose, and drug addiction more broadly, should be prevented regardless of any implications for transplantation. With this in mind, consider how the population of injection drug users shoulders a heavy burden of HIV, hepatitis B (HBV) and hepatitis C (HCV) (Table 1). First I will focus on screening guidelines, and then will move on to transplantation of organs known to carry an infection. table-1

Screening guidelines can help reduce the incidence of donor-derived infections, but the lab tests recommended in any policy must balance two potential concerns. First, lab tests have a rate of false negative results. Transplants of these organs will accidentally increase donor-derived infections. The policy question, then, is whether or not transplanting organs donated by individuals with higher risk of recent disease exposure will expose an unacceptable proportion of recipients to infection. This unintentional harm could undermine a duty of non-maleficence to organ recipients. Further complicating a potential screening policy is that the basic lab tests for HIV, HBV, and HCV detect the presence of human antibodies, which work well among a low-risk population, but antibodies might not appear in the blood until weeks after infection (Table 2).Recent infections are better detected by nucleic acid amplification (NAT) testing.To mitigate risk of infection,then, transplant screening policies should require a heightened level of surveillance among donors with a history of illicit drug use. Read More

Organs and Overdoses: The Numbers (Part I)

By Brad Segal

The surging opioid epidemic is a threat to the nation’s public health. This year the CDC reported that mortality from drug overdose reached an all-time high, with the annual death toll more than doubling since 2000. Yet in the backdrop of this epidemic, the country also faces ongoing shortages of a different sort–too few organs for transplantation. Every day, approximately 22 people die while waiting for an organ to become available. To some it is not a surprise–or at least not inconceivable–that the fastest-growing source of organ donors is being fueled by the national spike in drug overdoses. This first post will help delineate the scope and scale of the situation. My follow-up will discuss the ethical considerations and ramifications for public policy.

To start: the numbers. The Organ Procurement and Transplantation Network (OPTN) makes domestic transplant data publicly available online, which currently extends from 1994 to September 30th, 2016. Two decades ago, 29 organ donors died from a drug overdose.* In just the first nine months of this year, that number has climbed to 888 donors. Even with a quarter of the calendar year left to be counted, 2016 has already surpassed previous record set in 2015 (Figure 1).

figure-1
Figure 1

One might question whether this trend is an illusion–perhaps a rise in the incidence of donors who had overdosed reflects an increasing number of transplants. But the data suggest the opposite. Also plotted in Figure 1, the percentage of total organ donors who died from overdose (maroon diamonds, right-sided Y axis) has not remained constant–instead, the percentage has steadily increased. Two decades ago, overdose caused the deaths of 0.6% of all organ donors; this year, it is the cause of death among 12.0% of organ donors nationwide. The rising percentage means that not only are more victims of drug overdose donating organs, but that the pool of organ donors is increasingly composed of such individuals. Read More

Organ Transplant Malpractice and the “Proximate Cause”

By Alex Stein

Everyone interested in that area must read Shierts v. University of Minnesota Physicians, — N.W.2d — (Minn.App.2014), 2014 WL 7344014.

This important – yet, unreported – decision deals with a medical-malpractice action arising out of the patient’s death from cancer contracted from a donated pancreas. The trial court dismissed the action summarily based on the “proximate cause” doctrine, and the plaintiff appealed against that dismissal. Read More

Thinking about brain death

By Seema Shah

It astonishes me how many people do not realize the controversial nature of “brain death” and the fact that it is not the same as death. There is a substantial body of literature showing that brain death is not the equivalent of death. The President’s Council on Bioethics issued a white paper in 2008 acknowledging the deficiencies with our current approaches to determining death. The literature on the topic is fascinating—some brain dead individuals have gestated babies successfully to viability and gone through puberty. Many brain dead individuals can heal wounds, regulate their body temperatures, and persist on ventilators for many years. (If you are unfamiliar with this literature and want to read further, see the citations provided below.)

Frank Miller and I have argued that best the way to think about the status quo is that brain death is a status legal fiction, much like the legal construct that a corporation is a person. A corporation is similar enough to a person that it is convenient to treat corporations as persons under the law, rather than writing an entirely new body of law meant to apply to corporations alone. We have argued that brain death is similar to death—Frank Miller and Bob Truog express this by saying that a person who is brain dead is “as good as dead.” For this reason, we can ethically and legally treat the two states in the same way for the purposes of determining death and allowing vital organ transplantation.

There are many open and interesting questions about brain death that I will be exploring on this blog for the next few weeks. Michael Nair-Collins has a recent article in the Kennedy Institute of Ethics Journal that argues that the current approach to determining death in the U.S. is paternalistic and, presumably, unjustified. He cites as evidence the kinds of information that are shared with people deciding whether to become organ donors. But is this true, or is there evidence that the public is able to distinguish between brain death and death? Kenneth Kasper, Frank Miller, and I are investigating this at the moment, and we are finding some surprising answers in the literature. Read More