genetic engineering | The DNA Exchange

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by laurahercher | August 5, 2017 · 9:42 AM

Human Germline Editing: our crazy, scary, wonderful future is coming, but not quite yet

Publication this week of a paper by reproductive biologist Shoukrat Mitalipov and others put the subject of editing little baby humans front and center – above the fold news in the NY Times. Universally, the Mitalipov study was recognized as a milestone, and so it appears to be – a milestone on our journey to…wherever it is we are headed.

What did they do, and why is it important? Mitalipov improved greatly on previous efforts at germline editing, targeting embryos created using donor eggs and sperm carrying a pathogenic variant in the MYBPC3 gene associated with hypertrophic cardiomyopathy. Modification was successful over 70% percentage of the time, no off-target effects were detected, and only one of the 58 embryos was found to be a mosaic of altered and unaltered cells. While significant safety and efficacy concerns remain to be addressed, this work goes a long way toward validating the idea that, sooner rather than later, clinical use of this technology will be a realistic possibility.

The experiment raised hopes, but also some questions. CRISPR is often described as a DNA version of a search-and-replace function in a word processing program, but CRISPR itself only does search-and-remove. The ‘replace’ part leverages the cell’s own machinery for fixing breaks in DNA, and its innate penchant for tidying up any loose ends. Quick to the breach, cells can often be coaxed into using a template for the repair if one is provided along with enzymatic scissors and a guide RNA, allowing us to insert a custom DNA sequence. This bespoke DNA can be anything, but in this case it was meant to be a benign version of the MYBPC3 gene. In a surprising development, the cells preferentially ignored the synthetic template and used the unaffected version on the sister chromosome as a guide instead.

This had the desired effect of introducing a functioning wildtype gene, but if it is not overcome as a technical issue, will limit the range of what can be achieved via gene editing. This model doesn’t work at all with recessive disease, where there are two copies of the pathogenic variant. Additionally, it would not allow for the introduction of DNA sequences other than what is carried by a parental allele – a capability which is, I would argue, the truly unique feature of gene editing.

Articles about CRISPR may (and usually do) talk about its potential to prevent Mendelian diseases like Huntington’s or sickle cell, but we are already capable of preventing transmission of these diseases using IVF with PGD to identify embryos that are unaffected. Yes, as has been pointed out, this is not foolproof. A round of IVF may produce no unaffected embryos. In rare circumstances, one parent may be homozygous for an autosomal dominant disease. These are non-trivial events when they occur but they are rare and limited circumstances. For the rest, replacing one expensive and complicated technology with another is incremental progress at best, and not the reason why this story was A-1 on the NY Times website. Media interest, let no one be confused, was about the potential of CRISPR to produce what they referred to (inevitably) as designer babies.

Antonio Regalado of the MIT Tech Review decodes media coverage of human genome editing

Can the technology produce designer babies? This would be an easier question to answer if designer babies were actually a thing that you could define, but they’re not. Generally, what people mean by ‘designer baby’ is one created through any use of reproductive technology to ensure specific traits, as opposed to using identical technology to avoid diseases. The problem with this is that drawing the distinction is a bit of Impressionistic painting – clear from a distance, but blurring together when you get close. A number of articles this week suggested that designer babies can’t happen because traits are not something that can be manipulated by tweaking a gene or two (here and here). This is comforting but may not hold up. It’s fair to say that you can’t tweak general intelligence – but what about, for example, executive function? And while we’re on it, would that be increasing intelligence (bad) or avoiding ADHD and other mental health problems (good)?

But this is leading me into rabbit holes, where we debate what is or might be or could be possible, when just now I want only to say that the potential of gene editing to add an entirely new dimension to what we can currently offer is bound tightly to its ability to introduce DNA sequences that are different from what either parent can contribute. When we are able do that, we can expand the concept of what it means to ‘choose’ a child’s genotype. We can add rare variants that confer some protection or competitive edge. We can even contemplate adding synthetic variants designed in a lab and not borrowed from natural experiments. When move past embryo selection to embryo improvement, we will have our little Gucci baby whose possible existence causes so much consternation.

So does this week’s blockbuster paper put us closer to that day? Yes, because the technology has moved forward a giant step. Not that technology ever moves backwards, but the speed with which it has improved is staggering, and while momentum is not going to carry it over the remaining hurdles like a hot wheels car going loop the loop, it does make it easier to assume that all technological barriers will eventually fall. But at the same time, the template surprise reminds us that every step forward reveals another twist in the road.

Are we almost there? Who knows. If 2016 taught me anything, it was to stay out of the prediction game.

So what would a wise republic do? Coincidentally, a workgroup under the auspices of the American Society of Human Genetics published a paper yesterday in the AJHG laying out recommendations for public policy on human germline editing. The position statement was approved by ASHG, NSGC and 9 other organizations from six continents (full disclosure: I am one of the co-authors). The take home point is that modification of the human genome (egg, sperm or embryo) would be premature at this time but may be justified in the future, providing that there is a compelling medical rationale, an evidence base to support its use, ethical justification and a transparent public process to solicit and incorporate stakeholder input. In the interim, the organizations encourage governments to permit and to fund work like Mitalipov’s that investigates the potential of human germline engineering.

Having been a part of this group, I can attest that we thought long and hard about this aspect of the statement, and that we made it despite our concerns that this technology holds risks for both individuals and society, including the potential to increase existing inequities in health and quality of life. We may try and regulate use and norms such that we get the upside and not the downside, but we must acknowledge that to a large extent the two are inextricable.

Speaking only for myself, I can say that I see the allure of a form of intervention that might prevent rather than merely treat sickness and suffering, even as I sympathize with those who worry about the impact of the technology on future generations. If the choice were mine, it would be a difficult choice. But in the end, what I recognize is that we are not given a choice between going backwards and going forwards. The truth is that gene engineering is going to happen. No one government or individual is going to stop it — the world is too big and the stakes are too large. The questions that sit in front of us are not yes or no, but where, how and under what circumstances. I believe that a thoughtful society should engage with the technology, providing capital and oversight, resources and regulation. To turn our back is to sacrifice whatever leverage we could bring to bear as we establish norms for use, and to cede our leadership role in the scientific community at the dawn of an era, the start of a journey to…wherever.

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It’s A Slippery Slope. Get Over It.

This week, the FDA is holding hearings to examine the use of a new IVF technique that could allow women with mitochondrial disease to have children who are genetically their own without the risk of passing along the condition. The proposed treatment involves yanking out the nucleus of a donor egg and popping in a nucleus from the mom-to-be. Studies of monkeys have demonstrated that this method can be used to produce healthy monkeys; studies of humans thus far have demonstrated the potential to create what appear to be viable embryos. Shoukhrat Mitalipov, the Oregon-based researcher who has done both human and animal studies, is interested in moving to clinical trials – or as Dina Fine Maron puts it in Scientific American, “human clinical trials.”

The issue of oocyte modification was debated last year in the UK, where the government has opted to allow nuclear transfer to be used on an experimental basis. The story got major play in the press there, as it has here, with catnip headlines about ‘3-parent babies.’ There are some serious questions to be answered about the risks – the first studies using human eggs showed an increased rate of abnormal fertilization, although zygotes with an appropriate number of pronucleii seemed to develop normally. Minimizing the risk of harm to any child born of this technique is an important focus of the regulatory agencies and if we can’t do it safely, we shouldn’t do it at all – which brings me to the other question under debate: should we do it at all?

Marcy Darnovsky of the Center for Genetics and Society, a non-profit organization that leans precautionary on the use of reproductive technologies, has been waging a one-woman war against nuclear genome transfer, protesting the UK decision in Nature, circulating a petition to the FDA to decry human germline modification and penning an OpEd for the N.Y. Times entitled “Genetically Modified Babies.” Darnovsky brings up safety issues but the heart of her objection is the slippery slope argument. We have informally agreed not to make changes in the germline that will be passed down to subsequent generations – not to tinker with eggs and sperm. This is a step over that line. If we do this, what else will we do? It could, she says, “open the door to further germline manipulations.”

Last winter, I attended a panel on the ethics of germline manipulation where participants debated a resolution to prohibit genetically engineered babies. Lee Silver (Princeton) and Nina Farahany (Duke Law) represented the anti position (i.e., let’s NOT prohibit genetically engineered babies) and won the debate by focusing on – wait for it — nuclear transfer for mitochondrial disease! Forbid genetic engineering, they argued, and you rule out this potentially game-changing therapy for afflicted families hoping to give their kids a life free from the burden of life-long, incurable disease. In other words, another slippery slope argument, only the other way round – accept the concept of regulation in any form, let the bureaucrats in, and you cut yourself off from progress and doom families forever to suffering that could have been prevented.

The thing is, I am not at all convinced this example – like many other models we construct — represents anything other than itself. I don’t mean to say it’s trivial. But mitochondrial replacement therapy isn’t a reasonable stand-in for the complex issues associated with genetic engineering, like trait selection or eugenics. You can make the case that mitochondria are more like the bacteria we harbor in our gut than they are like nuclear DNA , in terms of how they affect our health and well being. Gut bacteria have DNA too. If we gave the 3-parent child a fecal transplant, would we have a 4-parent child? (Is that a bad thing? Cool or creepy?)

The problem with slippery slope arguments is that they don’t relieve the obligation to assess each and every situation on its own merits. They don’t provide some easy moral clarity or regulatory guidelines. Everything exists on some sort of continuum, whereby you can draw a straight line from the ludicrous to the patently unacceptable. When does life begin? It’s a tightrope, with one end tied around infanticide, and the other clasped in the hand of some guy out of a Monty Python sketch singing “every sperm is sacred.” Every decision we make is about drawing a line. And every ethical quandary worthy of the name is unique enough that it deserves its own weighing of the pros and cons.

Are you concerned about doing PGD for later-onset conditions? This is a line some people have suggested, between what is a good and a bad use of preimplantation technology. What if that condition is Huntington’s? Okay, what if it is a BRCA 1 mutation? Or what if it is a subtly increased risk of Parkinson’s disease? Each of these is a very different scenario. Every family is going to experience those risks differently. The fact that you can draw a line from here to there does not automatically absolve you of considering the facts at hand in each case, the good that can be done, what stands to be gained, what may be lost. It’s very hard to take away happiness for one person based on what might (someday, somewhere, possibly, in a related case) happen to somebody else.

The thing is, it would be so much easier if we could find that certainty. Slippery slope arguments are a plea to make things stand still for a moment, so a person can get their bearings. Anyone who works in genetics can relate to that sentiment. But history is itself a slippery slope from a turbulent past to an uncertain future, and we don’t have the luxury of stepping off. So what should we do about nuclear transfer for mitochondrial disease? Well, let’s make a decision based on mitochondrial disease and the very sensitive nature of the human embryo, which may not take kindly to this manipulation. Let’s not make it the last word on anything. Let’s not pretend we are now for all time choosing to abandon sufferers to their fate, or opting for GATTACCA. It’s hard enough and scary enough without conjuring up the ghosts of battles to come.