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3-person IVF and Infertility: What Kind of Slippery Slope is This?

Posted by Leah Lowthorp on October 26th, 2016

3-person IVF and Infertility: What Kind of Slippery Slope is This?

Reacting to two breaking news stories about 3-person in vitro fertilization (IVF) in less than two weeks, Paul Knoepfler, professor and stem cell researcher at UC Davis, recently tweeted:

On September, 27, 2016, news broke that NYC-based fertility doctor John Zhang and his team had delivered a baby the previous April that they created using a controversial mitochondrial manipulation technique, also known as 3-person IVF, that results in an embryo with DNA from three people. The baby was born in Mexico in order to avoid US regulation, as Zhang explicitly admitted. Despite the multiple violations of medical ethics involved, the media craze that followed largely heroized Zhang, depicting him as a doctor altruistically seeking to prevent the transmission of mitochondrial disease.

The prevention of mitochondrial disease has been the core justification cited all along for permitting these controversial, high-risk techniques that represent a form of inheritable genetic engineering, also known as human germline modification.

Yellow sign showing stick figure falling with text: DANGER Slippery Slope Keep AwayOn October 10, news broke that Valery Zukin, a fertility doctor at the Nadiya Clinic in Kiev, Ukraine, had used 3-person IVF not to lower the risk of mitochondrial disease, but as a treatment for infertility.

The media in this case was surprisingly quiet, perhaps because Zukin had supplied no published evidence of his claim, although the BBC did publish a somewhat critical piece entitled “3 person baby ‘race’ dangerous.”

On October 19 Nature News reported a claim that yet another baby conceived using some kind of mitochondrial manipulation technique has been born, this time in China. A paper is said to be under review at another journal.

What kind of slippery slope is this? It’s been clear from the beginning of the controversy surrounding 3-person IVF that it would be difficult to control its commercial uses beyond disease prevention. This is especially true when it comes to introducing  these genetic manipulation techniques into the multi-billion-dollar global fertility industry, a venture that could be extremely lucrative for all involved. 

To what extent has anticipation of this possibility been part of the story from the start? While we can’t know for sure, here are several points that might help make this connection:

  • In the late 1990s and early 2000s, a precursor to 3-person IVF known as ooplasmic transfer, also known as cytoplasmic transfer, was developed for age-related infertility and put into use without clinical trials. In 2001, the U.S. FDA stopped the procedure after at least two dozen babies had been born, citing lack of evidence of safety and efficacy. No such evidence was produced at the time. On October 24, 2016, Reproductive BioMedicine Online published the first follow-up study of these children. Despite the inconclusive nature of the study, which the authors admit is based on limited, subjective survey data from only 75% of the children’s parents, and with zero follow-up testing of the children themselves, they conclude that the procedure has not produced any long-term effects.
  • In February 2012, Shoukhrat Mitalipov, professor at the Oregon Health & Science University, filed a patent for maternal spindle transfer (MST) as a technique for providing prenatal treatment for mitochondrial disease in humans. In November 2012, he founded MitoGenome Therapeutics to reportedly commercialize his work.
  • On February 25 and 26, 2014, the FDA held a public meeting to discuss using 3-person IVF techniques for “the prevention of  transmission of mitochondrial disease or treatment of infertility”. Although the FDA does not make information from its applications public, this strongly suggests that someone applied for permission to conduct clinical trials towards both of these aims.
  • In January 2015, Mitalipov and MitoGenome Therapeutics teamed up with Chinese stem cell banking company Boyalife and the Korean company H-Bion, led by disgraced cloning researcher turned dog-clone entrepreneur Hwang Woo-suk, to start a lab in China. In a Nature News article, Mitalipov described the collaboration as a way to move his 3-person IVF research forward, stating, “Fertility and mitochondrial disease are a big clinical opportunity.”
  • In February 2015, Mitalipov confirmed that he had requested permission from the FDA to conduct two clinical trials using 3-person IVF techniques in the United States, the first to treat mitochondrial disease and the second to treat age-related infertility.
  • In February 2016, John Zhang of New York City-based New Hope Fertility Center released a video in which he lauded the technique’s usefulness as a fertility treatment, only briefly mentioning its potential use in the prevention of mitochondrial disease (see video at 3:05). This video was released only a few months before Zhang and his team delivered the aforementioned baby in Mexico for a Jordanian couple at risk of transmitting Leigh Syndrome.
  • In September 2016, Norbert Gleicher, a fertility specialist at the Center for Human Reproduction in New York City, says he sought a meeting with the FDA to discuss 3-person IVF for U.S. patients, including as a treatment for infertility.

CGS and others have criticized moving forward with 3-person IVF, even to prevent the transmission of mitochondrial disease, because of the unknown health consequences for resulting children and future generations, because safer options for forming families are already available, and because permitting mitochondrial manipulation in humans could open the door to other forms of human inheritable genetic modification. Throughout the policy considerations in the US and the UK about these techniques, the notion that they would be taken up as a treatment for infertility has been downplayed as unlikely or even fanciful. Yet here we are. When fame and fortune come into play, the slide can become very slippery indeed.

Previously on Biopolitical Times:

Image via Flickr

Dangers of an Unscientific Policy Process:
Why the UK’s legalization of “three-person babies” should not be the model for CRISPR

Posted by Jessica Cussins, Biopolitical Times guest contributor on October 25th, 2016

Dangers of an Unscientific Policy Process: Why the UK’s legalization of “three-person babies” should not be the model for CRISPR

Several researchers around the world have now turned the CRISPR genome editing craze towards human embryos, reigniting questions around the feasibility, legality, and morality of creating genetically modified humans. Some have suggested that we look for guidance to the United Kingdom’s policy process for “mitochondrial replacement,” also known as “three-person IVF,” which culminated in the world’s first legalization of a procedure that is technically a form of heritable human genetic modification in 2015.

How did the UK come to enable techniques that arguably contradict a policy in force throughout Europe for more than 15 years?

Having followed the process for several years, I would argue that we can learn a great deal from its history, but more specifically in what not to do moving forward in the CRISPR policy debate. In this blog, I will try to explain why.

I am a UK citizen who generally respects Britain’s regulatory models. However, I believe this process failed to live up to its self-image of openness and transparency. The experience taught me that science and technology hold such ingrained cultural and economic capital that people often hear any concern raised – even when it comes from other scientists – as “anti-science” or “anti-technology.” Moreover, it taught me that simple stories can become so compelling and satisfying that they do not bend, even in the presence of critical new information.

In this case, a consequential law was altered on the basis of a group of scientific methods whose human health and safety consequences have not been vetted, and could end up harming those they were designed to help. For those of us paying attention, this was not a great surprise. There were readily apparent data suggesting this outcome all the way through. The question is, why was this not enough to have shifted the policy process when it mattered? And how can we protect the children now being created around the world by researchers recklessly racing to beat the UK at its own game?

First, some breaking news

On September 27, a US team of fertility doctors told New Scientist they had produced a child at a clinic in Mexico whose starting cells were engineered using what they described as “spindle nuclear transfer”, otherwise known as the maternal spindle transfer (MST) mitochondrial manipulation technique. The team was led by Dr. John Zhang (based in New York City; working in Mexico because “there are no rules there”) who performed the procedure for a Jordanian couple at risk of transmitting Leigh syndrome.

Two weeks later on October 10, New Scientist broke a second set of claims from Valery Zukin, a fertility doctor working in Kiev, Ukraine. Zukin claimed he had used the pronuclear transfer (PNT) technique and implanted the resulting embryos in two women currently pregnant in their third trimesters.  Unlike the Zhang team, Zukin claimed he was using mitochondrial manipulation techniques to address “embryo arrest,” a general infertility issue not directly related to mitochondrial DNA mutations.

On October 19,  Nature News reported on further commentary from Zhang and Zukin at recent fertility conferences, and also broke the news that a scientific journal was considering whether to publish a paper documenting the use of mitochondrial manipulation techniques to produce a live birth in China. The same day, Zhang published a brief report in Fertility and Sterility.

These developments are arguably not unpredictable in the wake of the reckless hype and minimization of the techniques’ unknowns that occurred in the UK.

Second, some background on UK law

According to the UNESCO International Bioethics Committee who considered these issues in its follow-up to the UN’s Universal Declaration on the Human Genome and Human Rights, and the Council of Europe’s Convention on Human Rights and Biomedicine (the “Oviedo Convention”), human germline modification is considered medically unnecessary human experimentation that is contrary to human dignity. UNESCO recommends a moratorium on human germline engineering, and 29 nations have ratified the legally binding Oviedo Convention prohibiting the same.

The United Kingdom, like every country that has considered regulation on the matter, has a legal prohibition against making genetic modifications to human sperm, eggs, or embryos because such changes alter the human germline and thus every human born thereafter (as opposed to somatic gene therapies, which only affect a single consenting individual.)

However, a group of researchers at Newcastle University working on somatic cell nuclear transfer (i.e. cloning to create embryonic stem cells for therapies) thought that they might be able to use the same mechanism for a more immediate human application. There are a small number of women – in the range of 1 in 5,000–10,000 – who have what is called mitochondrial disease. This covers a number of issues that impact the functioning of the mitochondria, leading to wildly divergent conditions and outcomes. In about 15% of these cases, the problem is caused by the mitochondrial genome (which has 37 genes of its own and makes up a small fraction of the estimated 20,000 genes present in every cell of our bodies.)

Mitochondrial DNA is passed on solely through the maternal line, so if a large proportion of a woman’s mitochondrial DNA carries mutations, she may be at risk of passing them on to her children. Researchers at Newcastle (as well as several others around the world) came up with the hypothesis that in these cases, women who wanted to have genetically related children, but avoid this risk of mitochondrial disease transmission, could use nuclear transfer.

How do the techniques work?

A specialist would remove eggs from the intending mother’s body, and obtain eggs from another healthy woman, then combine them to use the nucleus from the first with the mitochondria and cytoplasm from the second. At some point sperm would be directly injected. Any resulting child would thus end up with DNA from three people (leading to this technique being referred to as “three-person IVF” or to the creation of “three-person embryos”). Scientists have tended to prefer the terms “mitochondrial replacement” or “nuclear genome transfer.”

Does this sound complicated? It is. Technically, legally, socially, and morally. But complicated doesn’t get laws changed. And, given that these techniques result in a genetically modified embryo, which is illegal in the UK, these scientists had to lobby for a change in the law in order to continue their work clinically. So they did lobby, for numerous years. And, in February 2015, they succeeded in carving out an exception to the law for this specific purpose.

It now turns out that their “pronuclear transfer” technique doesn’t work as expected. Mutated mitochondria can still carry over, and can lead to a host of problems. No child has yet been born using the PNT technique, but Valery Zukin claims two such children are expected in Ukraine in early 2017 (see breaking news above). The same cannot be said for the similarly under-researched MST technique which was reportedly used by John Zhang (using the term “spindle nuclear transfer”) to bring the child born on April 6, 2016 into existence. Even as these cases were being reported, researchers were searching for new variations that might avoid the numerous safety concerns surfacing in animal model research using these two techniques.

What kinds of problems emerged before the UK decision, and who knew about them?

The Human Fertilisation and Embryology Authority (HFEA) is the UK’s regulatory body for UK fertility clinics and for research involving human embryos. It led the charge to change UK law in order to enable embryo engineering licenses. Its process for assessing “mitochondrial replacement” included three separate reviews of the scientific methods over four years, and one public consultation to gauge public sentiment. Were members of the HFEA aware of any concerns?

The short answer is yes. A number of civil society groups, including the Center for Genetics and Society, raised concerns with them on numerous occasions, as did many scientists and researchers.

For example, in March 2014, David Keefe, The Stanley H. Kaplan Professor and Chair of the Department of Obstetrics and Gynecology at NYU Langone Medical Center, wrote to the HFEA to inform them of his concerns. He told them that his own lab, which was the first to report using mitochondrial manipulation techniques in mammals, had determined it to be unsafe for use in humans. He wrote:

Our own group moved away from this research because PGD [preimplantation genetic diagnosis] provides a relatively safe alternative to MR [mitochondrial replacement] for the majority of patients, and because vexing concerns linger about the safety of MR, including the safety of reagents employed during MR, carryover of mutant mtDNA during MR and disruption of interactions between mtDNA and nuclear DNA (nDNA).

For more information on the kinds of concerns raised by scientists around the world, see this compilation from the Center for Genetics and Society.

The HFEA’s own scientific reports also turned up some issues. For example, the first scientific review determined primate testing to be a necessary pre-requisite to human testing. A subsequent review found that a group of US researchers had tried PNT technique in primates and that it didn’t work. Instead of heeding this red flag, the HFEA simply dropped the primate requirement altogether.

Moreover, the HFEA defined their public consultation as highlighting “broad support” for the techniques in question. However, independent analysis of the consultation found that the majority of people who responded to the only open segment were actually against the law being changed at that time for a range of scientific and ethical concerns. That did not stop the HFEA from claiming the opposite, or from pushing forward.

So, how was the law changed?

The problems with the UK policy process seem to stem from a number of factors. For one thing, it apparently involved a commitment to the story that had taken hold, to a pre-determined end goal. While that goal surely began with the desire to help women with a rare disease, it seemed to become primarily a question of changing the pre-existing law. Everything was done in order to see that law changed. The time, money, and resources spent throughout multiple sectors of society were enormous.

As a particularly telling case in point, there was the sustained effort to control the language used in the public debate. The common term “mitochondrial replacement” is itself a euphemism because it is not the mitochondria, but the nucleus containing more than 20,000 genes, that is transferred. One scientist commented early on that such “scientifically inaccurate descriptions have been instrumental in easing the way to public acceptance of these manipulations.”

Perhaps even more brazenly, the Government’s Department of Health later came out with the position that the technique did not constitute “genetic modification”. This led to other scientists straight-out accusing the Government of dishonesty in its efforts to gain support for these techniques.

An additional factor enabling this process was a mistaken cultural assumption held by some policymakers, that helped them to hear all objections as “theoretical religious concerns.” This allowed them to diminish the myriad technical, social, and ethical concerns being voiced. One evolutionary biologist at an evidence hearing held by the UK Parliament’s Science and Technology Committee in October 2014 tried to raise his concerns about the techniques’ safety and efficacy at the meeting. He tweeted afterwards:

Thought on @CommonsSTC meeting: what's the point of funding, performing, publishing and requesting scientific evidence if it's then ignored?
— Ted Morrow (@ted_morrow) October 22, 2014

I described my own frustrations about this meeting in a blog at the time here.

A third factor that enabled the law to be changed seems to have stemmed from pride in seeing the UK as an innovation hub in the biomedical sciences, and in embryology in particular. At the evidence hearing, for example, Conservative MP Jane Ellison stated that she is “extremely proud” that Britain is a “pathfinder” and “innovator” with a “well-respected regulatory regime.” Similar sentiments were frequently voiced as part of the argument for proceeding.

What can we learn from this?

In the end, public trust has been compromised and patient’s hopes were repeatedly raised and then dashed, and now are being stoked again with the recent birth announcements – despite a startling lack of safety evidence about the health consequences for the resulting children. In my mind, this is exactly the kind of thing that threatens one’s position as a “respected” “pathfinder.”

But this turn of events was not necessary, and we can learn from the experience.

Because policy tends to move so much slower than technological innovation, it can be tempting to push for policy changes before important specifics are determined or tested. But the goal in creating policy around consequential science and technology must be to make it as responsive to changes in the data (both technical and social) as possible. If a new drug for Zika shows promise, its approval should be sped up; if it turns out that an alternative method for preventing transmission of disease is preferable, then that alternative should be pursued instead. When the technology is particularly risky or ethically problematic, its use should be especially carefully considered, and any potential alternatives taken very seriously.

We must continuously work to make sure we are driven by real, human needs. The push for technology for its own sake (or for the general sake of research or innovation) can be powerful, but it must not be the primary driver of public policy.

In this case, commitment to a thorough and adaptive learning process would have spotted failures and inefficiencies of the mitochondrial manipulation techniques much earlier on, and probably pivoted resources towards improved preimplantation genetic diagnosis as the safer and more efficacious method to prevent the transmission of mitochondrial disease. This kind of continuous learning may seem like more work up front, but it will save money, time, and maybe even lives in the long run.

The way we tell stories matters. The world’s first legalization of a form of heritable human genetic modification will always be a precedent. And how that history is recorded could have profound implications for how the future unfolds. The global consequences of the UK’s breach of a scientific and ethical global consensus are only beginning to be felt.

What should we do about CRISPR?

As the world scrambles to determine how best to govern human applications of genome editing, people are seeking instructive precedents. Many are looking to the UK’s “mitochondrial replacement” policy process as a prime model.

In a Cell report titled, “Going Germline: Mitochondrial Replacement as a Guide to Genome Editing,” Eli Y. Adashi and I. Glenn Cohen, professors of Brown Medical School and Harvard Law School respectively, provide just one example. They write:

Both [techniques] must contend with breaching the germline barrier. Both entail the manipulation of a human embryo. Both must address significant safety concerns. Both must engage a skeptical public… Applying the principles relied upon in the regulatory evaluation of [mitochondrial replacement] will go a long way toward assuring that the prospect of therapeutic genome editing in the human is the subject of a thorough, inclusive, ethical, safety-minded, and confidence-inspiring process.

Compared to the US context of piecemeal efforts by the FDA, but no explicit regulatory body for fertility clinics and embryo research, the existence in the UK of the HFEA and public consultations represent important improvements. But this process was far from exemplary. The creation of policy for the most consequential emerging technologies would benefit enormously from a commitment to scientific rigor, openness to a diversity of views, and adaptability.

Although the UK’s process for legalizing “mitochondrial replacement” may seem robust on its surface, the reality was that all dissenting views and unfavorable scientific results were sidelined, if not ignored. A façade of “rigor” that enables those in power to cherry-pick data and orchestrate public opinion may in fact be the most dangerous option of all. This is particularly true when the hype engineered to support legislative change is exported by forum-shopping doctors who seek to work in countries where “there are no rules”. When it comes to crafting policies for CRISPR germline genome editing, we must do better to put first the health, safety, and ethical treatment of women and children. We will need greater transparency and respect for inclusive debate to guide us towards responsible innovation in the life sciences.

Previously on Biopolitical Times:

Image via Pixabay

Just What We Need: Slicker Infertility Marketing

Posted by Gina Maranto, Biopolitical Times guest contributor on October 21st, 2016

Untitled Document

The most unsettling line in the recent Forbes article on the ambitious infertility startup Prelude comes about halfway through. “The IVF industry in the United States,” writes Miguel Helft, “has everything private equity likes—scale (about $2 billion annually) and growth (more than 10% a year), along with being fragmented and having outdated marketing.” 

In an era with precious few opportunities for double digit returns, why not turn the reproductive health sector into the next big thing by furthering its consolidation and selling services using lifestyle content?  “Hey,” Prelude’s hipster-chic splash page calls out, “how’s your fertility doing?” 

A woman in a polka dot blouse lounging on a couch looks directly in the camera with the text "Hey, how's your fertility doing?" in bright font.

If that piques your interest, scrolling down takes you on a kind of virtual stroll through the streets of Williamsburg, Wicker Park, or the Mission District, where you encounter edgily coifed, tatted, and bespectacled folk who presumably are spending as much time thinking about their reproductive fitness as they do their next Americano or Kimchi taco.  But you’ll find scant information about financial, psychological, or medical risks of egg retrieval (unless you count the presumed donor pictured alongside the quotation “I was worried about the discomfort, but seriously, it was no worse than a bikini wax—and for a much higher purpose”) or about failure rates after eggs are thawed and implanted.  Everything is upbeat and empowering, geared toward the “millennial mindset of health, wellness, and control.”

Prelude is targeting 20 to 30 year olds and the main product it’s selling them is their own eggs and sperm on ice.  The site proclaims, “If you are in your 20s or early 30s, there is no better time than now to bank your eggs and sperm. They are stretchy and full of reproductive life force, just like you!” (Must be all that hot bikram yoga, huh?) 

A woman with spectables and a backpack in a city street looks into the camera, with the text "Press Pause" in bright font.

With $200 million in funding, Prelude founder, chairman, and CEO Martin Varsavsky, who bills himself as a “serial tech entrepreneur,” laid the foundation of the company by acquiring controlling stakes in one of the largest IVF clinics in the country, Reproductive Biology Associates in Atlanta, which in 2016 had net sales of just over $5 million; and their partner, My Egg Bank, which gives would-be parents access to frozen eggs through a network of infertility clinics.  Already profitable, Prelude also offers a product line for 40-somethings in the form of “screened donor eggs.”  Helft writes that Prelude’s aim is “to take [egg and sperm freezing] mainstream, giving it scale and Silicon Valley pizzazz.” 

It all puts one in mind of nothing so much as the international market in animal sperm and embryos.  Reproductive technology in animals far predates that in humans: British scientist Walter Heape (himself a serial entrepreneur) produced the first successful mammalian embryo transfer in 1890 with rabbits.  By the mid-1960s, animal sperm banks could be found around the world, and one study estimated that the cattle industry had by then performed artificial insemination on 59 million cows, 47 million ewes, 1 million sows, 125,000 mares, 56,000 goats, and 4 million turkeys.  Businesses like Bovine Elite, Cattle Visions, and Cattle Genie are part of a multimillion-dollar global trade in cattle semen and embryos that has all but eliminated traditional mating and led to stacked pedigrees and reduced genetic variability.   (One Wisconsin bull who sired some 500,000 offspring made national headlines when he died.)

While American Society of Reproductive Medicine guidelines currently suggest limiting the use of a single male’s sperm to 25 recipients (there are no suggested limits for donor eggs or embryos), what’s to say we won’t see the human version of cattle breeding as marketing takes precedence and consumer demand drives clinical practice?  History provides ample evidence of the ways in which global capital tends to push enterprises toward greater scale and homogeneity—from fast food to pop culture to higher education.

Fifty years from now, historians could look back and see that Prelude, along with other egg banking and IVF-clinic networks duking it out for international market share, laid the groundwork for branded gametes and embryos, all under the soothing guise of offering customers “insurance” on their reproductive viability. 

Gina Maranto is a fellow at the Center for Genetics and Society. She is Director of Ecosystem Science and Policy and Coordinator of the Environmental Science and Policy program at the University of Miami's Leonard and Jayne Abess Center. Her articles, opinion pieces, and reviews have appeared in Discover,The Atlantic Monthly, Scientific American, The New York Times, and other publications. She is the author of Quest for Perfection: The Drive to Breed Better Human Beings.


Previously on Biopolitical Times:

Images via Prelude Fertility and Pixabay

World Bioethics Day: Human Dignity and Human Rights

Posted by Leah Lowthorp on October 19th, 2016

Untitled Document The first World Bioethics Day, sponsored by the UNESCO Chair in Bioethics, is taking place on October 19. This year’s theme of Human Dignity and Human Rights will be celebrated in 55 countries worldwide (see here for a list of participating countries and here for a list of planned events).

While most countries are hosting one or two World Bioethics Day events, India has planned a whopping 29. The only event scheduled in the United States is at Indiana University Northwest, which will include presentations on bioethics and human rights and a screening of “No Más Bebés,” a documentary about Mexican-American women who were coercively sterilized at Los Angeles County-USC Medical Center in the 1960s and 1970s. (Filmmakers Virginia Espino and Renee Tajima-Peña joined CGS on the UC Berkeley campus in 2016 to screen the film as a part of the Being Human in a Biotech Age series. They were also interviewed for the CGS online series Talking Biopolitics by eugenics scholar and CGS advisory board member Alexandra Minna Stern, see here and on YouTube.)

Human dignity and human rights, in addition to being the theme of this first annual World Bioethics Day celebration, form the primary framework of most of the international and national legislation worldwide that prohibits inheritable genetic modification, also known as human germline modification. The most notable among these is the Council of Europe’s 1997 Convention on Biomedicine and Human Rights (see here for a global list of national legislation banning inheritable genetic modification).

It is surprising that human genetics has such a low profile among the list of World Bioethics Day events. 2015 and 2016 have seen unprecedented technological developments with troubling implications for human germline modification – such as the public policy controversies surrounding reproductive applications of gene editing and human experimentation with mitochondrial manipulation techniques (or “three-person IVF) in Mexico and the Ukraine.

Out of 88 events today, only one sponsored by the Bosnia and Herzegovina Unit features genomics as its main theme. Five others, two in Italy and one each in Slovenia, Macedonia, and India, will include individual presentations on the wider topic of human genetics. The Bosnia and Herzegovina event is Bioethics in the Era of Genomics and Personalized Medicine, an international conference that will take place in Sarajevo on October 28.

Previously on Biopolitical Times:

Image via UNESCO

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