Ethical Dilemmas

Recent scientific advances have made possible the reprogramming of ordinary adult cells, such as skin cells, into undifferentiated, or so-called pluripotent, stem cells that can become many other cells, tissues or organoids. The technique promises to unravel intractable diseases, ranging from developmental disorders to neurodegenerative conditions such as Alzheimer’s, and lead to new therapies, including cell replacement and organ repair.

Emerging evidence, however, reveals that under certain conditions such reprogrammed cells could acquire biological features similar to those seen in the earliest stages of human embryonic development, a situation that sparks ethical questions.

Writing in eLife on March 21, a team of Harvard Medical School scientists call for the development of guiding principles to address this cluster of rapidly emerging ethical challenges created by advances in synthetic biology.

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The Harvard team was among many in the world working to develop and perfect tissue-engineering techniques when it first encountered indications of tissue developing embryolike features. Then a pivotal experiment conducted elsewhere and published in 2014 brought the Harvard team to the realization of the broader ethical implications of this work. In that experiment, synthetically engineered tissue showed a so-called primitive streak, a trait that heralds the formation of central nervous system in embryos.

The primitive streak develops roughly 14 days after fertilization, and current guidelines prohibit the research use of any human embryos past day that point.

Yet, there are no comparable guidelines for research with synthetic tissue made of reprogrammed adult human cells, which leaves researchers operating in a gray zone.

That gap, the HMS team writes, should be closed now, before any red lines are crossed.

“Emerging research in synthetic tissue engineering cannot be fully and meaningfully addressed by current ethical frameworks and the guidelines that emanate from them,” said John Aach, the lead author on the paper and lecturer in the Department of Genetics at HMS.

Scientific advances have often emerged before society has had a chance to grapple with their ethical implications. Past examples include in vitro fertilization, now a common practice, and the development of recombinant DNA—genetic material obtained from various organisms. Recombinant DNA is now used in a range of therapies, including hepatitis B vaccine, insulin for the treatment of diabetes and anticlotting factors for people with bleeding disorders.

The authors emphasize that human synthetic tissue bearing features of early embryonic development is not anywhere close to an actual embryo. Yet, they caution, given the speed at which science is moving forward, scientists are bound to encounter more and increasingly challenging instances of engineered tissue mimicking embryonic features.

“Nobody would mistake these human tissue samples for an embryo but they bear certain molecular features reminiscent of one so we need to figure out how to tackle these situations,” said HMS geneticist and synthetic biologist George Church, senior author on the article. “Where is the threshold of ethical concern? This question is far too big for scientists to answer, so we’re hoping to stimulate a broad conversation that involves professional organizations, ethicists, policymakers and the society at large.”

The HMS team calls for an entirely new set of guidelines, specifically formulated to address the biological idiosyncrasies of human synthetic tissue.

Current embryo research guidelines—written in the 1970s and updated periodically thereafter—cannot meaningfully address the range of scenarios and ethical conundrums bound to arise in years to come. This is because human synthetic tissue made from reprogrammed adult cells may develop differently from embryonic tissue, the authors say. Such critical differences in biologic behavior, they add, render current embryonic research guidelines inapplicable in cases involving synthetic tissue.

For example, the newest engineering techniques are already making it possible for scientists to develop tissue that progresses to neural development without the telltale primitive streak, rendering the 14-day rule an unreliable gauge for the onset of nerve tissue development. In other words, human synthetic tissue may develop features of concern without the established hallmark that signals the experiments should be stopped.

“Current guidelines use the primitive streak as a stop sign, which works for human embryonic development because it progresses along a well mapped-out, linear trajectory,” Aach said. “But synthetic tissue doesn’t necessarily develop the same way. Moreover, advances in synthetic biology may allow synthetic tissue to ‘travel off road,’ bypassing the road sign and veering into restricted territory.”

The new guidelines, the researchers caution, would apply only to synthetic tissue that can raise ethical concerns—such as neural tissue or reproductive cells—and not to just any lab-engineered cells. Liver tissue, for example, would be of no concern in this case, they say.

“It is critical to get the boundaries right because synthetic tissues are invaluable for research,” Church said. “They allow scientists to study the mechanisms of disease and test possible treatments without using invasive methods in humans.”

Additionally, synthetic tissues with embryonic features may provide the only way to study serious disorders that arise during embryonic development, the team says.

The new guidelines should, at a minimum, include the following:

• A catalog of morally concerning features. Researchers say that a central goal of the new guidelines should be to come up with a catalog of features or events associated with the development of what bioethicists refer to as “moral status,” which may include early signs of sentience, the formation of a heartbeat or the emergence of neural tissue. Using moral status as a trigger point instead of the primitive streak would provide guidance in situations where synthetic tissue doesn’t show this developmental signpost. Mapping the territories of moral concern and deciding what rules should apply to synthetic tissue, the HMS team says, will require scientific, social and philosophical inquiries, led by bioethicists and scientists from various disciplines.
• Definition of biological markers that signal emergence of moral triggers. The team says the identification of moral triggers should be predicated on the correct identification of the biological features that herald their onset. Identifying these biologic markers would provide researchers with concrete “safety margins” to operate within.
• Wide-ranging, open-ended questions as a conceptual foundation. Given the unprecedented nature of the newest scientific developments and their ethical complexity, the team says that the process of drafting a set of guidelines should be preceded by a wide-ranging exploration that stimulates and invites diverse opinions and viewpoints from different disciplines, traditions and institutions. Once the conceptual groundwork has been laid down, the team says, a formal committee could be assembled to draft guidelines.

Any new guidelines, the scientists conclude, should aim to address the ethical dimensions of synthetic tissue research without unduly hindering scientific exploration.

“The quest to understand human development and human disease and to formulate therapies for them should be carefully weighed against the moral concerns that arise in the course of these scientific inquiries,” says co-author Jeantine Lunshof, philosopher and ethicist in the Department of Genetics at HMS and an assistant professor at the University of Groningen in the Netherlands. “The time to start the conversation on how to achieve that is now.”