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Babies from Two Bio-Dads?

Posted by Pete Shanks on


A possibly significant piece of science was published in Cell online on Christmas Eve, but no one much noticed for a couple of months. It carried this unprepossessing title:

SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate

The Wellcome Trust, which supported the project, didn't even put out a press release, but the University of Cambridge did, explaining it concisely:

Scientists at the University of Cambridge working with the Weizmann Institute have created primordial germ cells — cells that will go on to become egg and sperm — using human embryonic stem cells. Although this had already been done using rodent stem cells, the study, published today in the journal Cell, is the first time this has been achieved efficiently using human stem cells.

Two months later, Lois Rogers of the London Sunday Times caught on that these were artificial gametes, interviewed some of the scientists and published a piece titled

Cell breakthrough to bring two-dad babies

A senior co-author, Jacob Hanna of the Israeli Weizmann Institute, went so far as to suggest that the technique might lead to a baby "in just two years." (Other experts are not convinced; the phrase "total baloney" has been used.) And from there, the story hit Newsweek and a flurry of headlines.

Artificial gametes have been a source of discussion for so long that a recent survey in Human Reproduction turned up 2424 articles. Indeed, the UK HFEA has had a backgrounder on the subject for at least five years; the use of "in-vitro derived gametes" for reproduction is prohibited in the UK, and the creation of embryos for research would require a license.

The recent paper is an incremental step. The research is real, and the science is interesting, particularly (as the journal article title suggests) in the discovered difference between mouse and human development. But it would be a very long way from this development to any kind of practical use.

There might eventually be some medical value derived from this work, but don't hold your breath. Moreover, as Paul Knoepfler notes, "there’s a 'dual use issue' here. This same kind of technology, if applied by some rogue scientists, could be used to clone human beings as well." Knoepfler goes on to remind us that the United States has no formal policy prohibiting human reproductive cloning, and that it's "probably well past time" for one to be put in place.

The techniques could also facilitate human germline genetic modification, also not regulated by law in the US. Both human reproductive cloning and germline modification are prohibited in dozens of other countries.

As long ago as 2008, Marcy Darnovsky wrote in the San Francisco Chronicle, when a rodent experiment made similar headlines:

Why are speculative and risky technologies being held out to lesbians and gay men as tantalizing prospects? Are reproductive methods that amount to dangerous experimentation on their children really a road to freedom for gay families? Or is the language of equality and empowerment being used to justify human experimentation that puts these children at great risk?

Previously on Biopolitical Times:






Mitochondrial Mission Creep and the Cloning Connection

Posted by Pete Shanks on February 14th, 2015


Shoukhrat Mitalipov

On Tuesday February 3, the UK House of Commons voted in favor of legalizing nuclear transfer so that a small number of women with a particular subset of mitochondrial disease could try to have unaffected and genetically related children. The British press headlined it the next day, and the rest of the world's media then caught on that this was a Very Big Deal. The Associated Press report noted that:

While this legislation was drafted specifically to grant permission only for certain specified techniques, critics fear it will encourage scientists to push for other experiments in the future.

No, no, said supporters on both sides of the pond. "This is not a slippery slope," UK Public Health Minister Jane Ellison insisted. Susan Solomon of the New York Stem Cell Foundation agreed. Bioethicist Arthur Caplan also discounted worries about the slippery slope. So did the MP Frank Dobson, in the Commons debate.

Really? We didn't have to wait a week.

On Sunday February 8, British newspapers reported that Shoukhrat Mitalipov of the Oregon Health and Science University (OHSU), who pioneered a variation of the techniques in question, had asked the FDA for permission to start clinical trials of it in order to treat age-related infertility. This concept is not new: It was part of the FDA discussions in February 2014, critiqued and dismissed, and discussed again last summer. Nor is it a surprise that Mitalipov applied, though this may be the first public announcement.

Here's the fun part (#1): Mitalipov told The Independent that "We hope [the UK vote] will help in the US, and hopefully the FDA will move faster." In response, said the UK Telegraph:

if the technology was made available to infertile women in America, there would be growing pressure for Britain to follow, experts said.

This is what's technically known as a Trans-Atlantic Cross-Ruff.

(The term was coined to describe the early career of the American actress Raquel Welch, who arrived in the UK with publicity claiming she was the newest Hollywood bombshell, made a movie in which she wore a fur bikini, and returned home as the newest Hollywood bombshell.)

And here's the fun part (#2): Bioethics Professor John Harris not only supports the idea (he supports pretty much everything techno) but insists that

"It could not be argued this is further down a slippery slope for the simple reason the slippery slope applies to the extension of the technique, not to the use of the same technique for another therapeutic purpose — and treating infertility is recognised as a therapeutic purpose."

Off-label use of human germline engineering? No problem!

But wait, there's more! Here's the real fun part (#3): Just two days later, on February 10th, Science Insider published this story about Mitalipov:

Stem cell pioneer joins forces with stem cell fraudster

Yes, that means the notorious Korean scientist, Hwang Woo-suk. The guy who claimed to do what Mitalipov actually did do — custom-make embryonic stem cells. The "fake it till you make it" guy who got caught fabricating data, embezzling public funds and abusing women to get at their eggs. The disgraced guy who has been trying hard to rehabilitate his reputation for a decade. The guy who does clone dogs and wants to clone a mammoth. The guy who desperately hopes to get his license to work with human cells back from the Korean authorities.

Mitalipov tried to walk the story back a bit the next day in Nature, insisting that he was "baffled by reports that he and Hwang would be collaborating on academic research." Hwang would be collaborating with the Chinese company Boyalife on animal husbandry, he said, while Mitalipov would collaborate with Boyalife on non-human primate work. And the $93 million investment mentioned in the Science article? News to him! "I was very surprised to see all those zeroes," says Mitalipov. "We've only had one small meeting."

That doesn't square with Hwang's version, which Science translated from an interview with the Korean Dong-A Ilbo:

Mitalipov's "strength is in primate stem cells. My specialty is in cell nuclear transplantation. So we've agreed that if we combine his strength with mine, we can create a breakthrough outcome in curing maternal line genetic disease, on which he is now focusing," the paper quotes Hwang as saying.

It's entirely possible that Hwang is — to use another technical term — bullshitting. But even so, what on earth was Mitalipov thinking? The kindest interpretation is that he is frustrated that he cannot immediately move into human clinical trials in the U.S. But why take up with a disgraced fraudster? Why let himself be photographed shaking hands with Hwang? The picture is dated January 13, and Mitalipov seems to have kept quiet about it, so presumably he suspected he might face criticism. So … what was he thinking?

Media reaction to these new wrinkles has so far been quite muted, especially compared to the hubbub that accompanied the UK vote. There is no evidence that Mitalipov's proposal is having an effect in Parliament (the House of Lords is yet to vote), and most people seem to have drawn a discreet curtain over the cloning connection. Stem-cell scientist and blogger Paul Knoepfler, on the other hand, called Mitalipov and Hwang "The Odd Couple of Cloning Research" and described the venture as "a major development." Which it may turn out to be.

Presumably, Mitalipov did not actually intend to provide an illustration of the slippery slope. But it's hard not to see it.

Previously on Biopolitical Times:





Of Clocks and Mammoths: The Pitch for De-Extinction

Posted by George Estreich, Biopolitical Times guest contributor on February 9th, 2015


Untitled Document

Introduction

De-extinction raises a host of questions: ethical, practical, philosophical. But for advocates, there’s a rhetorical question as well: How do you persuade a lay audience to support the project? That persuasion involves special challenges: one has to explain and normalize a complex technology, answer ethical objections, and make a radically new approach to nature seem emotionally “right.”

De-extinction has been much discussed in print, but the most complete case for the project is made at the website of Revive and Restore, a nonprofit dedicated to “genomic conservation”; their “overall goal,” in their words, is “enhancing biological diversity and ecological health worldwide.” Revive and Restore—the project of environmentalist, entrepreneur and Whole Earth Catalog founder Stewart Brand, and his wife, Ryan Phelan—touts, sponsors, and helps to coordinate several hoped-for restorations, including the heath hen, the passenger pigeon, and the woolly mammoth. In TED talks and other forums, Brand has been a passionate advocate of de-extinction.

Revive and Restore’s webpages are artful and complex: words, images, and video combine and reinforce each other, and appeals to reason and emotion are interwoven. The total effect of these strategies is to present de-extinction as an ideal route to an ideal outcome; in doing so, however, the persuasion tends to erase or minimize complexities, both technical and conceptual. To see how this works, let’s take a closer look, beginning with the smallest unit: the word chosen to describe the project.

Prefixes, nouns, and frames

The word “de-extinction”—neutral, scientific-sounding—frames the discussion in a powerful way. That power resides largely in the prefix.

1. The prefix assumes a central and debatable premise: that extinction can, in fact, be reversed. If this premise is accepted, then conceptual questions (would an engineered approximation count as a revival? is it right to revive an Ice Age creature on a rapidly warming planet?) become secondary to technical ones (what is the best way to bring species back?). To Brand’s credit, he has engaged with these questions publicly; but they are clearly secondary to the project of revival, which has already begun.

2.  The prefix also frames the technology as positive, opposing it to “extinction,” just as the word revival links it to life. At the same time, the coinage gives the reader a foothold in the familiar, linking synthetic biology to the known. This tactic is used throughout the webpages, which is filled with words like revive, restore, rescue, conservation, comeback. Often these words are paired with a technical word (“genomic conservation,” “genetic rescue”). These phrases position science and technology as saviors, not threats.

As a result, a complex world of ideas and choices is divided into simple alternatives: extinction or de-extinction, loss or rescue.  This is the beginning of persuading people to adopt one alternative, and not the other.

What’s next? Filling in the frame with a picture.

Images: filling in the frame

On a well-designed webpage, words and images work together. That’s true of the Revive and Restore home page, where reproduced paintings show us images of the species to be restored, including a composed still life of lost species, with the passenger pigeon front and center; an image of a single pigeon, soaring in the sky; and a picture of a woolly mammoth in fisheye perspective, its majestic tusks dominating the foreground, the curvature of the earth barely visible behind it. The mammoth is, in Brand’s terms, “iconic.”  These images are informative, in that they show us species that are lost; but their true function is persuasive: they help the viewer imagine an ideal outcome of the de-extinction experiment.

In context, however, a digital reproduction of a painting is more than a little ironic. Though the lush realism of the image evokes another century, a time when many extinct species were alive and abundant, the image functions differently in practice: digitally reproduced, distributed on the Internet, viewed on screens, the images are computer-dependent reproductions used to advocate for computer-dependent reproductions. (In the large composed still life, we can “mouse over” lost species to learn more.) 

The emphasis on the visual is a function of the medium. But this medium privileges the beauty of individual members of species over other things harder to represent: less beautiful species that matter more in an ecosystem (like, say, bees); groups of animals (it’s ironic that we see a single pigeon, and not flocks); and ecosystems themselves. But the emphasis on the visual is also driven by the economics of restoration. To paraphrase a recent interview with Brand, mammoths are easier to fund than mice: “As architects say, form follows funding. The animals that will draw avid supporters who have avid amounts of money will probably be the first ones that get dealt with.”

An idealized process

Persuading the public to approve of new technologies entails explaining those technologies. That explanation, however, has a persuasive bent. We can see this tendency in a clever graphic on the Revive & Restore site: the “extinction continuum.”

This graphic gives form to the project’s central premise. Like the word de-extinction, the graphic implies that species can be restored in their original state, while linking that premise to the power of biotechnology (“How Biotechnology Can Help” is the caption). It’s also deftly constructed, and more complex than it first appears.

In the graphic, both living and lost creatures are recognizable silhouettes, as if to emphasize the uncertain status of threatened or theoretically revivable species: present yet absent, gone but not lost. Only one creature—the dinosaur, with “no DNA” available—appears as a skeleton. The other animals, whether extinct or still living, are rendered in shades of gray. That, and the ability to see all the creatures in a single image, makes it almost as if the extinct creatures are still present—thus making “revival” imaginable, as if the pigeon simply needed to follow the green arrow back to “recovering.”

And yet the arrows, though graphically parallel, are conceptually askew. One (the red) is factual. The other (green) is hypothetical. Therefore, the diagram blurs the distinction between fact and projection. It is fact that the passenger pigeon is extinct; whether it is “revivable” is hypothetical, and “reintroduction” and “recovering” extend the hypothesis. Fact and optimistic projection coexist in the same image.

That optimism reaches its zenith in one of Stewart Brand’s selling points for reviving the mammoth: ameliorating climate change. In a short essay reproduced on the Revive and Restore site, Brand writes, “[The mammoth’s] return to the north would bring back carbon-fixing grass and reduce greenhouse-gas-releasing tundra.” In this paradigm, the mammoth—an engineered creature—will itself become an agent of geoengineering. Created to live on the earth, it will also alter the earth in a beneficial way.

Apart from the optimism cascade required to believe that synthetic mammoths will help lower the Earth’s temperature, the scenario displays a fundamental tension in the de-extinction project: it is sold with the rhetoric of restoration and preservation, but driven by an ethic of engineering and control.

Blockbuster resurrections

To sum up: de-extinction frames the issues with a deft use of naming, establishes a vivid picture in words and images of a desired outcome, establishes biotechnology as the sole route to that outcome, and portrays the technology itself in a positive light.

Similar patterns are visible in the persuasive tactics used for other technologies, including noninvasive prenatal testing and mitochondrial transfer. But the pitch for de-extinction has a distinguishing feature: what I call a “blockbuster aesthetic,” a belief in visual spectacle, technical impressiveness, the project’s sheer size—and perhaps even its expense—as proofs of value.

The “revival” of the woolly mammoth, and of the passenger pigeon, closely resembles a Hollywood movie: the revival and restoration of the Jurassic Park franchise, for example, or (as historian of science and medicine Anita Guerrini suggested to me) Avatar.

As with those movies, the relaunch of the species is closely associated with a larger-than-life, charismatic auteur. And as with those movies, the return of lost species is meant to awe and overwhelm. In Stewart Brand’s narrative, these effects have a moral purpose:  

Such animals can also serve as icons, flagship species inspiring the protection of a whole region. 

and:

Conservationists are learning the benefits of building hope and building on hope. Species brought back from extinction will be beacons of hope.

The return of the marvelous marsupial wolf called the thylacine (or Tasmanian tiger), extinct since 1936, would ensure better protection for its old habitat.

The returned species, in other words, will be living persuasive tools. Images in the present will inspire action to “bring back” species; those species will then themselves inspire further action. What is hoped for, then, is a feedback loop of persuasion.

“The Long Now”

What troubles me most about the paradigm Brand promotes is the naïve idea of interpretation at its heart: the belief that the creature, once authored, will be understood, even decades from now, precisely as its creator intends. That naïveté is present in another, seemingly unrelated project of Brand’s Long Now Foundation: The 10,000 Year Clock.

This clock, a massive device composed of “marine grade 316 stainless steel, titanium and dry running ceramic ball bearings,” and currently being built inside a West Texas mountain, is meant to “creatively foster long-term thinking”: pilgrims, hiking miles to the clock, will witness it and presumably think about time in a different way. (They will also need to help wind it occasionally.) From the Long Now’s home page:

Such a clock, if sufficiently impressive and well-engineered, would embody deep time for people . . . . Ideally, it would do for thinking about time what the photographs of Earth from space have done for thinking about the environment. Such icons reframe the way people think.

Like a living mammoth, the clock’s sheer scale is meant to elicit a specific idea. The idea of “deep time,” expressed by the phrase “The Long Now,” is an interesting one—and, like the reversal of a tragic extinction, difficult to oppose in principle.

And yet I see a second meaning in the phrase “The Long Now.” The 10,000 Year Clock and the revival of lost species are meant to demonstrate taking the long view beyond our present moment. But it seems to me that they do precisely the opposite: they extend specific, local, cultural values associated with our time and place—and, even more specifically, with Silicon Valley—into the foreseeable future. In the uncritical belief in technological solutions, in the belief in size and spectacle, in the exalting of computing power that bridges both online persuasion and the engineering of new genomes, “The Long Now” may mean something other than its authors intend.

George Estreich received his M.F.A. in poetry from Cornell University. His first book, a collection of poems entitled Textbook Illustrations of the Human Body, won the Gorsline Prize from Cloudbank Books. His memoir about raising a daughter with Down syndrome, The Shape of the Eye, was published in SMU Press’ Medical Humanities Series. Praised by Abraham Verghese as “a poignant, beautifully written, and intensely moving memoir,” The Shape of the Eye was awarded the 2012 Oregon Book Award in Creative Nonfiction. Estreich lives in Oregon with his family.

Previously on Biopolitical Times:





FDA Regulation and Early Prenatal Testing

Posted by George Estreich, Biopolitical Times guest contributor on February 5th, 2015


Editors' note: The US Food and Drug Administration is currently considering regulation of laboratory developed tests (LDTs), which include noninvasive prenatal tests. The comment here was submitted to the FDA by George Estreich, as part of a comment period that closed on February 2. The FDA's materials on LDTs can be found here.

To the Food and Drug Administration:

I’m writing to urge the FDA to regulate the new, noninvasive prenatal tests, and I wish to focus particularly on health claims being made in the advertising for the tests. If prenatal testing is to be of greatest benefit both to individual women and to society at large, the information that accompanies that testing should be accurate, complete, useful, and most of all nondirective. The ads for NIPT do not meet these criteria. As a result, the advertising has a number of potential adverse consequences for consumers.

Beth Daley’s recent investigative report in the Boston Globe offers a disturbing look at the consequences of misinformation: as Daley notes, when both health professionals and patients believe that the test is “99% accurate,” as it is often advertised to be, both false positives and false negatives have serious consequences for prospective parents’ state of mind, and for the course of an intended pregnancy. Believing the test to be accurate, women have aborted healthy fetuses in the case of a false positive, or have carried fetuses with severe conditions to term.

These beliefs are mistaken, but they are completely understandable, given the expertly executed ads for the technology. Though the figure “99%” is ubiquitous in the ads, whether referring to sensitivity, specificity, or “accuracy,” the number of true interest to a consumer—the positive predictive value—is either in fine print, or difficult to find. As genetic counselor Katie Stoll has pointed out, the PPV—the chance that a positive is a true positive—ranges from around 50% accurate in the case of the most common conditions, to the single digits in the case of some of the microdeletion screenings now being offered. In some cases, the claim of accuracy is supported by the factually inaccurate claims that “fetal DNA” (or even “your baby’s DNA”) is tested directly. (It is placental DNA that is tested; the occasional mismatch between fetal and placental DNA likely accounts for false results.)

Misleading statistical claims are accompanied by powerful emotional appeals. The ads for NIPT are rife with images that provide emotional content, but no clinical information: beautiful pregnant women and chromosomally normal children. These images, along with risk-laden descriptions of the conditions to be avoided, establish an emotional, value-charged implicit argument for the test.

Indeed, even the name “noninvasive” is part of a coordinated marketing campaign. The companies contrast the test with amniocentesis and CVS, whose risks are repeatedly highlighted. And yet this approach may mislead. Since NIPS is not a diagnostic test, but a screening test, a positive result will require confirmation by invasive techniques. Therefore, it is troubling to see NIPS framed as an alternative. There’s a further danger too: in emphasizing the miscarriage risks of amnio and CVS, while presenting NIPS as accurate, the ads may discourage women from using the truly diagnostic test available to them.

In the ideal world, women would receive accurate, complete, and nondirective information to accompany a prenatal test. They would also have access to a genetic counselor or other expert health professional to help them interpret results. But the ads for NIPT are the opposite of this ideal: they are covert, using emotional appeals and misleading statistics; and they are, by definition, directive, in that their aim is to get consumers to opt for an expensive, proprietary test.

Because of the size of the market, the potential health consequences of this advertising are extensive. False results may lead to avoidable anxiety, and even to irreversible outcomes. In addition, the ads may undercut the relationship between healthcare provider and patient, requiring the provider to explain where the ads exaggerate. Regulating advertising for NIPS can therefore result in better outcomes for patients.

George Estreich received his M.F.A. in poetry from Cornell University. His first book, a collection of poems entitled Textbook Illustrations of the Human Body, won the Gorsline Prize from Cloudbank Books. His memoir about raising a daughter with Down syndrome, The Shape of the Eye, was published in SMU Press’ Medical Humanities Series. Praised by Abraham Verghese as “a poignant, beautifully written, and intensely moving memoir,” The Shape of the Eye was awarded the 2012 Oregon Book Award in Creative Nonfiction. Estreich lives in Oregon with his family.





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