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Slippery Slopes and Biological Curve Balls: Updates on 3-person IVF

Posted by Leah Lowthorp on December 13th, 2016


Black and white image of woman's silhouette looking at her phone while pushing baby carriage in a European city

In September the world learned of a US fertility doctor who had gone to Mexico where “there are no rules” in order to arrange the birth of a child conceived using 3-person in vitro fertilization (IVF), technically a form of human germline modification, to prevent mitochondrial disease. In October we learned that 3-person IVF is being used experimentally in the Ukraine to treat infertility.

In November we saw four additional important developments:

1) The media got 3-person IVF all wrong

On November 1, Reproductive Biomedicine Online published “Setting the Record Straight,” the journal’s editorial response to the “shoddy scientific journalism” surrounding an article in the very same issue. The article in question was a report on the apparent health of children born in the late 1990s and early 2000s using cytoplasmic transfer, a 3-person IVF precursor (see here for CGS’s take on the media coverage of that article). Published in the immediate aftermath of the Mexico and Ukraine cases, most media reports took it as evidence that current 3-person IVF techniques (pronuclear and spindle transfer) are safe. Railing against this misinterpretation, the editor argues that:

the technique of cytoplasmic transfer in the late 1990s is so different from those of pronuclear or spindle transfer as to make the apparent normality of the offspring born through the former technique of little relevance in the context of (the latter).

In other words, the media got it all wrong—the study doesn’t prove anything about the current or future safety of experimental 3-person IVF techniques.

2) Slippery slope: Disease prevention to fertility treatment

With all focus in September on the use of 3-person IVF to prevent mitochondrial disease, the slippery slope toward the multi-billion dollar fertility industry and a potential normalization of human inheritable genetic modification is unfolding right before our eyes. On November 10, a study co-authored by Shoukhrat Mitalipov, who has developed and promoted one of the 3-person IVF variations, was published in Stem Cell proposing the introduction of 3-person IVF technology as a fertility treatment. Characterized by one of the co-authors as “just one additional advance over IVF,” the new study promises a two-for-one deal for aging women to “increase the yield … available for transfer from a single stimulation cycle.”

As opposed to other 3-person IVF techniques that transfer the nucleus from an intending mother’s egg into a donor egg from which the nucleus has been removed, the new variant would use the genetic material from an intending mother’s polar bodies, small cells produced during oogenesis that contain nuclear DNA but that typically don’t develop into eggs that can be fertilized. Reconstructed eggs generated with this so-called “polar body nuclear transfer” technique would pose as much risk to any resulting child as other 3-person IVF methods, and the overt shift toward using such a biologically extreme procedure to address basic infertility is deeply troubling.

3) Moving ahead at all costs

On November 30, the UK’s Human Fertilisation and Embryology Authority (HFEA) released their Fourth Review by an independent panel of experts, examining the safety and efficacy of 3-person IVF techniques for the purpose of avoiding serious mitochondrial disease. The review recommends “cautious use” of these techniques for “carefully selected patients” in cases “where there are no acceptable alternatives” such as pre-implantation diagnosis (PGD), and supports mitochondrial DNA (mtDNA) haplotype matching as a precautionary measure. It concludes that reversion, the phenomenon whereby carried-over “faulty” mtDNA multiply faster than donor mtDNA and eventually take over the donor egg, does not pose a serious risk despite evidence to the contrary. It also rejects a U.S. National Academy of Medicine report that recommends limiting clinical research to the transfer of male embryos so as to avoid inheritable genetic modification, and emphasizes the importance of long-term follow-up.

The Science Media Center issued a collection of expert reactions to the review the same day that was predominantly celebratory. Dr. David J. Clancy of Lancaster University, however, strongly questioned the panel’s seeming impetus to move forward at all costs, even in light of serious ongoing safety concerns. He wrote:

[3-person IVF]’s sole benefit is to allow affected women to have healthy children who bear half their genes. The best alternative is IVF by donor egg... [T]he evidence now suggests that, at some point, producing a child who will suffer from mitochondrial disease is a certainty. Are we, as a society, OK with that?

The HFEA is set to consider the issue at a meeting on December 15.

4) A biological curve ball

Also on November 30, another study co-authored by Mitalipov was published in Nature that suggests that reversion (see #3 above) is a serious problem related to “mismatches” between the mitochondrial DNA of the intending mother and that of the egg-provider. The authors propose an as-yet-tested system of mtDNA replication-rate matching that would allow the egg provider’s mitochondria to remain dominant in the developing embryo. Karen Weintraub’s coverage in Scientific American recognized the hurdle this poses for clinical uses of 3-person IVF technology, describing it as “a biological curve ball” that shows that mitochondrial diseases “can come back to sicken a child, even when 99 percent of the mother’s own mitochondria are eliminated.” Most media reports, however, managed to spin this setback as progress (see here, here and here).

Within the span of only a few short months, we have seen a disturbing trend toward the normalization of an experimental technology that is still widely considered unsafe, and whose implications for future generations are yet unknown. CGS and others have criticized the clinical application of 3-person IVF, even to prevent the transmission of mitochondrial disease, because of the potential serious health consequences for resulting children and future generations, because safer options for creating families are already available, and because allowing mitochondrial manipulation in humans could open the door to other forms of human inheritable genetic modification, banned in more than 40 countries worldwide. 

Previously on Biopolitical Times:

Image via Pixabay





Trump, Science and Social Justice

Posted by Pete Shanks on December 8th, 2016


President elect Trump is standing at a podium, looking above.

Untitled Document

It has not escaped our notice that the specific process we have witnessed in the last month immediately suggests a possible alteration of the regulatory and ideological landscape. As with genomics, however, the devil is in the details and many of them remain obscure. Some general outlines have emerged, and they are frightening to anyone who cares about social, economic or environmental justice.

It seems certain that the Electoral College will confirm Donald Trump as the winner of the Presidential Election, although a few “faithless electors” might cast protest votes. It is absolutely certain that Hillary Clinton won the popular vote; at this writing, she is leading by 2,7 million votes and seems likely to have attracted more votes than any Presidential candidate in history except then-Senator Obama in 2008. Nevertheless, Trump and Vice-President-elect Mike Pence are not only claiming a mandate, they are backing their talk up with extraordinarily reactionary appointments.

In part, this may be down to Trump’s inexperience: He seems to be picking people he knows. And GeneralsReuters is running a list of top appointments, and Nature had a useful summary of possible science-related appointees last week. But what other criteria does he have?

Eugenics, apparently:

All men are created equal; well, it’s not true, ’cause some are smart, some aren’t. …  You have to have the right genes. … I’m a gene believer … I'm proud to have that German blood. There’s no question about it. Great stuff.

And white supremacy. Of course, that is denied, for instance by a founder of The American Conservative:

The United States is entering into [a] period of demographic transformation, where whites, politically and demographically dominant for all of the nation’s history, will become a smaller majority, and perhaps then a plurality. Whether this transformation will be assimilative or anti-white, peaceful or violent, remains to be seen. Those in the upper reaches of the Democratic Party throwing around loose charges of “white supremacism” are certainly doing nothing to make it go smoothly.

So what’s the nice, polite way to describe Steve Bannon, set to be Trump’s Senior White House Counselor, and former chairman of what the Southern Poverty Law Center has called a “white ethno-nationalist propaganda mill”? The New York Times gave it a go:

Mr. Bannon is in some ways a perplexing figure: a far-right ideologue who made his millions investing in “Seinfeld”; a former Goldman Sachs banker who has reportedly called himself a “Leninist” with a goal “to destroy the state” and “bring everything crashing down.” He has also called progressive women “a bunch of dykes” ...

Nope, can't be done.

But science, of course, is politically neutral. (Just the facts, ma’am.) So it should not be a concern that the Environmental Protection Agency will be run by a “close ally” of the fossil fuel industry, Scott Pruitt. Or that the Health and Human Services Secretary, Tom Price, has been focusing for years not just on dismantling the Affordable Care Act but also barring funds for Planned Parenthood; and opposing abortion. Or that running the Centers for Medicare and Medicaid Services will be Seema Verma, a close advisor of Pence, who worked to make Indiana’s Medicaid plan "one of the most punitive in the country.” 

It could get worse. The Food and Drug Administration may go to Jim O’Neill, a colleague of the execrable Peter ThielBloomberg notes:

O’Neill also could push the agency in new directions. In a 2014 speech, he said he supported reforming FDA approval rules so that drugs could hit the market after they’ve been proven safe, but without any proof that they worked, something he called “progressive approval.”

What could possibly go wrong? (Don’t all speak at once.) We should note that this is apparently a trial balloon. Scott Gottlieb of the American Enterprise Institute is said to be the other candidate. He has some FDA experience, under George W. Bush, but the editor of the New England Journal of Medicine said in 2005:

Gottlieb has an orientation which belies the goal of the FDA.

A quick glance at his Forbes columns shows he really hasn’t changed. But he regularly appears on Fox News, so Trump may know who he is.

The Union of Concerned Scientists are concerned enough to organize a 2300-signature letter, supporting “unfettered science.” Heads of 29 scientific societies (including the AAAS) politely called for a meeting to advise Trump. Another ad-hoc group of scientists called “Not Who We Are” has their own open letter, with climate scientist Michael Mann at the head of the list of signatories. They are all right, of course, but may be, um, waving into the wind.

To be fair, as we must, there is one surprising suggestion: Four key Republicans in Congress, all chairs of committees or important subcommittees, sent a letter to Trump urging the President-elect to keep Francis Collins as Director of the National Institutes of Health. Since Collins is a gentleman, there is no word of this on his blog or Twitter feed. But really, why would he need the grief?

Update: Francis Collins said on Friday, December 9, that he was flattered by the letter and would consider it a privilege to remain in his post.

Previously on Biopolitical Times:

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Review of Blame: A Novel

Posted by Abby Lippman, Biopolitical Times guest contributor on November 28th, 2016


Book cover of Blame by Tony Holtzman. Black and white illustration, in bird's eye perspective, of a maze with mice.

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Because it is a central theme of this novel, it seems appropriate for me to start this review with my own “conflict of interest” – or as I prefer to see it, my “competing interest.” So I note that my parents and Tony's parents were friends when we were young children and though he and I were never friends, we were colleagues in adulthood insofar as we attended the same medical/human genetics meetings and conferences and kept in touch with our separate critiques of these issues, even discussing them, when we met.

Readers, therefore, can make their own assessments of my comments about Blame as to whether or not they are “fair” or even unbiased. Readers should also know that though I have a long history of writing and publishing book reviews, both in print and online, with only one exception these have been works of non-fiction; critiquing a novel is something I vowed not to do once the first was complete, but here I am....

Enough about me; the book is what is important here, and it is an important book – especially for those who are not trained in or otherwise familiar with human/medical genetics and the range of ethical, social, legal, and political issues raised by the applications of what is learned in a lab. It is a novel of fiction and a novel of science, often eerily portraying not only what is happening now but what is possibly very soon to come as new technologies are normalized, “monetized,” and enter “ordinary” medical practice.

Blame is fueled by these issues, with the characters propelled by the concerns raised and their own ambivalences about what is “right” and useful to do. It is a kind of hybrid book, combining an introduction into the intrigues of (and intriguing nature of) genetic research with a compelling story of (some) good people who go – and are led – astray. Thus, while the characters are well-limned, they can at times seem to represent an issue at least as much as appear to be fully-fleshed individuals.  

As a result, the reader may feel, as I did, deeply drawn to but still hungry to know more about the central figure and his wife, in order to better understand just why he (a solid scientist doing careful research) and she (a strong woman with feminist leanings) do what they do. Unfortunately, to provide details here would likely give more away what readers should better discover for themselves. 

Watching the characters who incarnate a range of roles (investigative journalist, African-American woman harmed in a commercially-funded clinical trial, university administrators and faculty, et al.) also affects us strongly on gut levels but can nevertheless sometimes seem forced to meet Holtzman's political agenda when the latter is given priority over the deep development of characters per se.  Why do some key players make the turns in behavior and in practices that they do? Hubris? Insecurity?  Money? Love? All are at play, and we don't necessarily need these all spelled out. Yet while it's very clear that the central characters do change, it might enrich the novel if the why of this was easier to sense without feeling that some turns are plot-driven to make a point. 

But despite these quibbles, no doubt the book is a page-turner and the reader is driven along.

There is also no doubt that Holtzman has a stand on the issues he raises, a stand I probably almost entirely share with regard to the evils of profit-driven science, the corruption of academia and corrosive effects on science (and people and relationships) that ensue, the hyped promises of predictive medicine, the dilution of fully informed consent, and the lingering oppression of societal racism. He brings all this, including their historical grounding, into the novel with clarity and expertise.  And accompanying all this are generally easily digested details of genome analysis, medical interventions, and other “science” matters. As background these are essential elements of Blame; however, when these are foregrounded, they risk becoming ersatz major “characters.” This, in turn, can make some of the fictional people simply potential “issue-bearers,” embodiments, that is – but possibly with bodies that are thinner-than-needed to fully satisfy a reader.

Because it is a challenge for a reviewer to talk of the actual “plot” of the book without revealing its  ending, and wanting not to spoil the experience for readers, I will only note that there is lots here to keep a reader engaged and turning pages, perhaps even in one sitting. Blame is properly titled; much and many bear this load in the novel's exploration of how genetic testing of asymptomatic people can reveal DNA patterns suggestive of the later appearance of highly undesired diseases (in this book Alzheimer); of how lucrative for companies it can be to patent these DNA segments/patterns for the commercial development of tests they can sell; etc. To this are added references to other sources of blame: past racist research, sexual harassment, spousal violence, the lifestyles of rich and privileged whites in the US, inadequate even lax regulations and laws related to genetics and genetic technologies in law and legal regulations....a full set of the blameworthy from which to choose.

This book is as important to read and then discuss with others to foster the important public input into  decision-making re how genetic technologies are developed, funded, used, provided, and governed, as it is to read simply for oneself: it will surely give everyone several hours of pleasurable page-turning. I hope these two “applications,” the collective and the private, will merge– and Blame will be an essential basis for this merging as science continues to seek ways to read our futures and to extend lives. While a work of fiction, Blame is definitely not science-fiction.

Abby Lippman has spent decades following developments in applied genetic and reproductive technologies. Her main interests as a feminist researcher, writer and activist center on women's health and the politics of health. She is also Professor Emerita in the Department of Epidemiology, Biostatistics and Occupational Health at McGill University.

Image via Cloud Splitter Press





18 Years Later: First Update on Children Born Using 3-person IVF Precursor

Posted by Leah Lowthorp on October 27th, 2016


On October 26, an Associated Press story broke with the headline, “The Kids are All Right: Children with 3-Way DNA are Healthy.” Riding the wave of recent controversies surrounding 3-person in-vitro fertilization (IVF) in Mexico and the Ukraine, the widely syndicated article plainly misrepresents the source study, which as we shall see, is not at all certain of the reliability of its results.

On October 24, Reproductive BioMedicine Online published the first follow-up study of children born in the late 1990s and early 2000s using a precursor to 3-person IVF known as cytoplasmic transfer. Developed for age-related infertility, this technique, also known as ooplasmic transfer or transplantation, involves injecting mitochondria-rich cytoplasm from donor eggs into the eggs of intending mothers prior to fertilization. Fertility doctors used this experimental technique in human subjects without clinical trials, with at least two dozen babies born as a result. In 2001, researchers from St. Barnabas Medical Center in New Jersey published a study announcing live births resulting from this procedure, and claiming the world’s “first case of human germline modification.”

Scientists, medical professionals, and public interest advocates raised a number of serious concerns at the time, ranging from the children’s increased risk of severe mitochondrial disease resulting from mitochondrial heteroplasmy to ethical concerns about human inheritable genetic engineering. Shortly after the study was published, the U.S. FDA halted the procedure, citing lack of evidence of safety and efficacy and requiring clinics to seek the agency’s approval to continue. No such request was made at the time, and no formal studies to track the effects of this technique upon the resulting children were conducted.

The recent Reproductive BioMedicine Online study documents an attempt to follow up on the seventeen children, now ranging in age from 13-18, born as part of the St. Barnabas Medical Center research cited above. The study is inconclusive due to a number of serious limitations, including the fact that it is based entirely on limited email surveys completed only by parents. None of the children participated in the survey, nor were they subject to any follow-up testing. In fact, only one of them has been informed of their participation in this experimental procedure. In addition, the parents of quadruplets that represent 25% of the total number of children never replied to the survey. 

The authors are open about the flaws of their study, writing that it “is limited because the information from the quadruplet delivery is essential for providing firm conclusions,” and that their findings “are based on subjective assessment criteria and no standardized instruments were used.” In the end, the researchers conclude that they were unable to discern an effect of cytoplasmic transfer on the children, but attach the clear disclaimer, “but the power of the investigation was low.”

In light of this, it is disappointing that media coverage of the study was so unbalanced and celebratory. Mostly syndications of the Associated Press story mentioned above, it both severely downplayed the study’s frankly-stated limitations, and misconstrued the authors’ tentative conclusion as evidence that not only this specific technique but somehow all forms of mitochondrial manipulation are safe.

Previously on Biopolitical Times:

Image via Pixabay






 


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