Research Recant

Editors Note: This article appeared in Salvo 43, Winter 2017 edition and is used by permission.

 

Don't Believe Everything You Read—Even in Science Journals

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This is a cautionary tale on accepting announcements of scientific breakthroughs at face value. In late 2016, “fertility provocateur” Dr. John Zhang announced the first birth of a three-parent child, through a technique he called mitochondrial replacement therapy (MRT), one of three IVF techniques used to combine material from the eggs of two women and the sperm of one man.[i] The goal of such therapy is to avoid transmitting disease to a child through mitochondrial DNA, which is contained in the cellular material outside the nucleus of a woman’s egg. This international experiment involved Jordanian parents, an American team, and a clinic in Mexico.[ii]

Initial reactions focused on the success of the technique: the boy was born without the lethal disease. Some news reports acknowledged that the technique was controversial, and legal only in the UK. A few months later, a girl was born in Ukraine using a variation of the technique,[iii] this time involving embryo destruction. Again, the press reported the successful birth while noting that, despite the controversy over three-parent embryos, no laws had been violated.

Several months after the news accounts appeared, Reproductive BioMedicine Online published Zhang’s academic paper, accompanied by an editorial explaining the journal’s decision to publish it despite the study’s “weaknesses and limitations” and despite remaining “uncertainties concerning methodologies and results.”[iv] Three months later, a group of researchers associated with the Center for Human Reproduction (CHR) in New York did something quite uncharacteristic: in the pages of Reproductive BioMedicine Online itself, they lambasted the journal for publishing the study.[v] A few weeks later, the Food and Drug Administration (FDA) directed Zhang to stop marketing his procedure.

 

Questioning the “Breakthrough”

The CHR group pointed out that to call the three-parent baby an “achievement” was “a perfect lesson in how responsible research should not be performed.”[vi] Among other problems, the group noted that: informed consent was inadequate to the circumstances; the success and safety of the experiment were overstated; federal policy was breached; and institutional ethical approval was lacking, a fault that was not only unethical but that should have prevented publication of the study.

Although the authors also expressed concern that “opponents of reproductive research” would use Zhang’s “irresponsible” approach to generate prohibition of all reproductive research, it is to their credit that they publicly aired their disquiet. Their punch list of the problems with the experiment illustrates how easy it is to overlook and excuse questionable conduct when the ultimate goal is tantalizing, amazing, or desirable. It also challenges the typical response to sensational news: to skim the research papers, cherry-pick highlights, and share the news via social media without doing the hard work of understanding the science, investigating the claims made, and critiquing the methodology. Among the matters often glossed over are:

  • Terminology. What do the phrases used to describe or denote the procedures actually mean? “Mitochondrial replacement therapy,” the term preferred by researchers, sounds innocuous, even beneficial. “Three-parent baby” raises public concerns. Yet both terms refer to the same reproductive techniques. Similarly, “somatic cell nuclear transfer” often replaces “cloning,” which has more negative connotations.
  • Informed consent. Human subjects are protected by federal guidelines that require fully informed consent. The human subject (or his or her parent) must understand the short- and long-term risks of the experiment, alternative treatments, the discomforts it will entail, the possibility of unforeseeable negative consequences ensuing, the proposed benefits of the treatment, its safety, its efficacy or likelihood of success, and the extent of confidentiality that will be granted. All this information must be communicated in understandable language, not in jargon or legalese.

    When a child is involved, the medical researchers’ responsibility is even greater. In the case of the Jordanian baby, his parents withdrew their consent for follow-up monitoring and genetic testing, which suggests that their initial consent was not fully informed. They may not have been made aware of genetic drift, where mutations in mitochondrial DNA can accumulate over the years, a development they might well have wanted to know about. The outcomes of the three-parent experiment are uncertain at best. “It will take years, maybe decades, to determine whether the treatment in this case was successful or not,” the CHR group wrote.[vii] 

    The egg donor would also have needed to give informed consent, a detail missing from the report. Was she told about the intended experimentation with her eggs? Or did she think she was participating in a traditional egg retrieval?
  • Ethics approval and legal compliance. Initial stories reported that the procedure was carried out in Mexico, where it is not explicitly prohibited. But the CHR group pointed out that the actual IVF mitochondrial replacement took place in New York City, in violation of FDA rules. The embryo was then frozen and shipped to Mexico for transfer to the woman’s womb, with the couple later returning to New York for the birth. This convoluted arrangement was an obvious effort to skirt relevant laws. The Mexico IVF clinic allegedly gave ethics approval. Interestingly, virtually no IVF clinic in the U.S. has an institutional review board (IRB) for this purpose. Nor could a Mexican IRB approve the mitochondrial replacement procedure that took place in New York.

    FDA guidelines prohibit any genetic experimentation on eggs or sperm that results in live birth. The purposes of Zhang’s startup company, Darwin Life, would violate this policy.
  • Bait and switch? Although mitochondrial replacement has been hyped as a way to prevent the birth of a child with a serious or lethal disease, Zhang switched course immediately after the birth of the Jordanian baby. Darwin Life was formed to use the three-parent technique to rejuvenate the eggs of older women, by combining them with enucleated eggs from younger women.[viii] Zhang promises even more: genetic editing to select hair or eye color, or increase the child’s IQ. “Everything we do is a step toward designer babies,” he said. “With nuclear transfer and gene editing together, you can really do anything you want.”[ix]

 

Another Misleading Study?

The three-parent baby is not the only scenario where a glowing announcement has proven premature. In July 2017, Shoukhrat Mitalipov announced that his team had successfully edited genes in about 150 human embryos (later destroyed), to eliminate a heart condition that is fatal in a small number of otherwise healthy carriers. It now appears that the “genetic scissors” may not have snipped out the faulty paternal DNA and replaced it with healthy maternal DNA, as originally described.[x] Although what actually happened is still uncertain, one scientist hypothesized that instead of being edited, the embryos did their own “self repair.”[xi]

In addition, it is possible that larger segments of DNA—not just the faulty DNA—were deleted from the embryos. This means that other DNA portions may have suffered serious genetic damage. In another example of sloppiness in terminology, the phrase “gene editing” suggests a degree of precision that does not exist. “Genetic modification” better conveys the murkiness of research in this area.

 

Contagious Behavior?

Hubristic medical research is not exclusive to assisted reproduction. The pressure to achieve scientific breakthroughs is widespread. Not surprisingly, hype and sloppy methods infect many scientific studies, and some end up being retracted due to misconduct or outright fraud.[xii] Questionable research results can trap people in the web of inflated expectations.

The stakes extend beyond the potential harm done to research participants. Transgressing ethical standards designed to protect both patient and the public jeopardizes respect for scientists and support for research.

The lesson to be learned: Do not accept news reports of “breakthroughs” at face value. Rely on credible experts who soberly assess the data. Better yet, learn to read skeptically and investigate prudently.



Notes

[i] Emily Mullin, “The Fertility Doctor Trying to Commercialize Three-Parent Babies,” MIT Technology Review (June 13, 2017): http://technologyreview.com/s/608033/the-fertility-doctor-trying-to-commercialize-three-parent-babies.

[ii] The nucleus was removed from the presumably healthy egg of a donor, and replaced with the nucleus from the mitochondrial disease-carrying egg of the Jordanian mother, then fertilized with the father’s sperm.

[iii] Jason Dailey, “Second ‘Three-Parent’ Baby Born. This Time, It’s a Girl,” Smithsonian.com (Jan.19, 2017): http://smithsonianmag.com/smart-news/three-parent-technique-used-infertile-couple-first-time-180961870. The technique used in the Mexico case is called spindle transfer. In Ukraine, a technique called pronuclear transfer was used, where the nucleus is removed after fertilization.

[iv] Mina Alikani et al., “First Birth Following Spindle Transfer for Mitochondrial Replacement Therapy: Hope and Trepidation,” Reproductive BioMedicine Online (April 2017): https://doi.org/10.1016/j.rbmo.2017.02.004.

[v] Norbert Gleicher et al., “First Birth Following Spindle Transfer,” Reproductive BioMedicine Online (July 14, 2017): http://dx.doi.org/10.1016/j.rbmo.2017.07.006.

[vi] Ibid.

[vii] Ibid.

[viii] Mullin, “The Fertility Doctor,” note 1.

[ix] Mullin, note 1.

[x] Michael Reilly, “Human Embryo Editing Study Shows We Still Have a Lot to Learn About CRISPR,” MIT Technology Review (Sept. 1, 2017): https://technologyreview.com/the-download/608791/human-embryo-editing-study-shows-we-still-have-a-lot-to-learn-about-crispr.   

[xi] “4 Key Reasons Mitalipov Paper Doesn’t Herald Safe CRISPR Human Genetic Modification,” The Niche: Knoepfler Lab Stem Cell Blog (Aug. 7, 2017): https://ipscell.com/2017/08/4-reasons-mitalipov-paper-doesnt-herald-safe-crispr-human-genetic-modification.

[xii] See, for example, RetractionWatch.com. One report listed fraud as the primary reason for retractions, accounting for 43 percent of them. See “Study: Scientific Fraud on the Rise,” cbsnews.com (Oct. 1, 2012): http://cbsnews.com/news/study-scientific-research-fraud-on-the-rise.

 

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